Thiopyrimidine and isothiazolopyrimidine Kinase Inhibitors

ABSTRACT

Compounds having the formula  
                 
are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/392,951, filed Mar. 20, 2003, which claims priority to U.S.Provisional Patent Application Ser. No. 60/366,708, filed on Mar. 21,2002.

TECHNICAL FIELD

The present invention relates to compounds which are useful forinhibiting protein tyrosine kinases, methods of making the compounds,compositions containing the compounds, and methods of treatment usingthe compounds.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are enzymes which catalyse thephosphorylation of specific tyrosine residues in cellular proteins. Thispost-translational modification of these substrate proteins, oftenenzymes themselves, acts as a molecular switch regulating cellproliferation, activation, or differentiation. Aberrant or excessive PTKactivity has been observed in many disease states including benign andmalignant proliferative disorders as well as diseases resulting frominappropriate activation of the immune system (e.g., autoimmunedisorders), allograft rejection, and graft vs. host disease. Inaddition, endothelial-cell specific receptor PTKs such as KDR and Tie-2mediate the angiogenic process, and are thus involved in supporting theprogression of cancers and other diseases involving inappropriatevascularization (e.g., diabetic retinopathy, choroidalneovascularization due to age-related macular degeneration, psoriasis,arthritis, retinopathy of prematurity, and infantile hemangiomas).

The identification of effective small compounds which specificallyinhibit signal transduction and cellular proliferation by modulating theactivity of tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation, differentiation, or metabolism istherefore desirable. In particular, the identification of methods andcompounds that specifically inhibit the function of a tyrosine kinasewhich is essential for angiogenic processes or the formation of vascularhyperpermeability leading to edema, ascites, effusions, exudates, andmacromolecular extravasation and matrix deposition as well as associateddisorders would be beneficial.

SUMMARY OF THE INVENTION

In its principle embodiment the present invention discloses a compoundof formula (I)

or a therapeutically acceptable salt thereof, wherein

X is selected from the group consisting of —N— and —CR³—;

Z¹ is selected from the group consisting of —N— and —CR⁴—;

z² is selected from the group consisting of —N— and —CR⁵—;

Z³ is selected from the group consisting of —N— and —CR⁶—;

Z⁴ is selected from the group consisting of —N— and —CR⁷—;

R¹ is selected from the group consisting of hydrogen and NH₂;

R² is selected from the group consisting of alkoxy, cyano, hydroxy,nitro, —NR^(a)R^(b), and -LR⁸;

R³ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, arylalkyl, carboxyalkyl, halo, haloalkyl,heteroarylalkyl, (heterocyclyl)alkyl, hydroxyalkyl, (NR^(a)R^(b))alkyl,and (NR^(a)R^(b))C(O)alkyl;

R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consistingof hydrogen, alkoxy, alkyl, NR^(a)R^(b), halo, and hydroxy;

R⁸ is selected from the group consisting of alkoxyalkyl, alkyl, aryl,arylalkenyl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and (heterocyclyl)alkyl;

L is selected from the group consisting of —O—,—(CH₂)_(n)C(O)(CH₂)_(p)—, —C∉C—(CH₂)_(n)O—, —C(O)NR⁹—, —NR⁹C(O)—, —NR⁹—,—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—, —NR⁹C(S)NR¹⁰—, —NR⁹C(═NCN)NR¹⁰—,

—NR⁹C(═NCN)O—, —OC(═NCN)NR⁹—, —NR⁹SO₂—, and —SO₂NR⁹—, wherein each groupis drawn with its right side attached to R⁸, and wherein R⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen, and alkyl;

m, n, and p are independently 0-2;

provided that at least one of Z¹, Z², Z³, and Z⁴ is other than —N—.

In another embodiment the present invention provides a compound offormula (I) wherein Z¹ is —CR⁴—; Z³ is —CR⁶—; and Z⁴ is —CR⁷

In another embodiment the present invention provides a compound offormula (I) wherein X is —N—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—; Z⁴is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; and m is 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; and m is 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; L is selected from the groupconsisting of —(CH₂)_(n)C(O)(CH₂)_(p)—, —C∉C—(CH₂)_(n)O—, —C(O)NR⁹—,—NR⁹C(O)—, —NR⁹—, —NR⁹C(S)NR¹⁰—, —NR⁹C(═NCN)NR¹⁰—, —NR⁹C(═NCN)O, andNR⁹SO₂—; and m is 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; L is—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m is 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; L is—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is aryl; L is—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is selected from the groupconsisting of alkenyl, alkoxyalkyl, arylalkyl, halo, heteroarylalkyl,heterocyclylalkyl, hydroxyalkyl, and (NR^(a)R^(b))alkyl; R⁸ is aryl; Lis —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is (NR^(a)R^(b))C(O)alkyl;R⁸ is aryl; L is —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is hydrogen; R⁸ is aryl; Lis —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is alkyl; R⁸ is aryl; L is—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is alkyl, wherein the alkylis selected from the group consisting of ethyl, isopropyl, and propyl;R⁸ is aryl; L is —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n, and p are 0.

In another embodiment the present invention provides a compound offormula (I) wherein X is —CR³—; Z¹ is —CR⁴—; Z² is —CR⁵—; Z³ is —CR⁶—;Z⁴ is —CR⁷—; R¹ is hydrogen; R² is -LR⁸; R³ is alkyl, wherein the alkylis methyl; R⁸ is aryl; L is —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; and m, n,and p are 0.

In another embodiment the present invention provides a compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.

In another embodiment the present invention provides a compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea.

In another embodiment the present invention provides a compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea.

In another embodiment the present invention provides a compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.

In another embodiment the present invention provides a compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.

In another embodiment the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment the present invention provides a method forinhibiting protein kinase in a patient in recognized need of suchtreatment comprising administering to the patient a therapeuticallyacceptable amount of a compound of formula (I), or a therapeuticallyacceptable salt thereof.

In another embodiment the present invention provides a method forinhibiting KDR in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

In another embodiment the present invention provides a method forinhibiting Tie-2 in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

In another embodiment the present invention provides a method fortreating cancer in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

As used in the present specification the following terms have themeanings indicated:

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of one to six carbon atoms containing at least onecarbon-carbon double bond. Examples of alkenyl groups include, but arenot limited to, ethenyl, 2-methyl-1-propenyl, and 1-butenyl.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through an alkyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylcarbonyl,” as used herein, refers to analkoxycarbonyl group attached to the parent molecular moiety through acarbonyl group.

The term “alkyl,” as used herein, refers to a monovalent group derivedfrom a straight or branched chain saturated hydrocarbon. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl, andisopropyl.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicor tricyclic fused ring system wherein one or more of the fused rings isa phenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a cycloalkenyl group, a cycloalkyl group, or anotherphenyl group. Tricyclic fused ring systems are exemplified by a bicyclicfused ring system fused to a cycloalkenyl group, a cycloalkyl group, oranother phenyl group. Examples of aryl groups include, but are notlimited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the presentinvention can be optionally substituted with one, two, three, four, orfive substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfanyl, alkylsulfonyl, a second aryl group, arylalkoxy,arylalkyl, aryloxy, carboxy, cyano, halo, haloalkoxy, haloalkyl,heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroaryloxy,heterocyclyl, (heterocyclyl)alkyl, hydroxy, hydroxyalkyl, nitro,NR^(a)R^(b), (NR^(a)R^(b))alkyl, (NR^(a)R^(b))C(O),(NR^(a)R^(b))C(O)alkyl, and oxo; wherein the second aryl group, the arylpart of the arylalkoxy, the arylalkyl, and the aryloxy, the heteroaryl,the heteroaryl part of the heteroarylalkoxy, the heteroarylalkyl, andthe heteroaryloxy, the heterocyclyl, and the heterocyclyl part of the(heterocyclyl)alkyl can be further optionally substituted with one, two,three, four, or five groups independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylsulfanyl, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NR^(a)R^(b),and oxo.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one aryl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “carboxyalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one carboxy group.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic cyclicor bicyclic ring system having three to ten carbon atoms and one tothree rings, wherein each five-membered ring has one double bond, eachsix-membered ring has one or two double bonds, each seven- andeight-membered ring has one to three double bonds, and each nine-toten-membered ring has one to four double bonds. Examples of cycloalkenylgroups include, but are not limited to, cyclobutenyl, cyclohexenyl,octahydronaphthalenyl, and norbornylenyl. The cycloalkenyl groups of thepresent invention can be optionally substituted with one, two, or threesubstituents independently selected from the group consisting of alkoxy,alkyl, aryl, arylalkyl, cyano, halo, haloalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, nitro, —NR^(c)R^(d),and oxo.

The term “cycloalkenylalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one cycloalkenyl group.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to twelvecarbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[3.1.1]heptyl, andadamantyl. The cycloalkyl groups of the present invention can beoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkoxy, alkyl, aryl,arylalkyl, cyano, halo, haloalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, nitro, —NR^(c)R^(d), and oxo.

The term “(cycloalkyl)alkyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through an alkyl group.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one halogen atom.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. Thefive-membered rings have two double bonds, and the six-membered ringshave three double bonds. The heteroaryl groups are connected to theparent molecular group through a substitutable carbon or nitrogen atomin the ring. The term “heteroaryl” also includes systems where aheteroaryl ring is fused to an aryl group, a cycloalkenyl group, acycloalkyl group, a heterocyclyl group, or another heteroaryl group.Examples of heteroaryl groups include, but are not limited to,benzodioxolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl,furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxadiazolyl, oxadiazolyl, oxazolyl,thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl,and triazinyl. The heteroaryl groups of the present invention can beoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl,alkylsulfonyl, aryl, arylalkoxy, arylalkyl, aryloxy, cyano, halo,haloalkoxy, haloalkyl, a second heteroaryl group, heteroarylalkoxy,heteroarylalkyl, heteroaryloxy, heterocyclyl, (heterocyclyl)alkyl,hydroxy, hydroxyalkyl, nitro, NR^(a)R^(b), (NR^(a)R^(b))alkyl,(NR^(a)R^(b))C(O), (NR^(a)R^(b))C(O)alkyl, and oxo; wherein the aryl,the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, thesecond heteroaryl group, the heteroaryl part of the hetoerarylalkoxy,the heteroarylalkyl, and the heteroaryloxy, the heterocyclyl, and theheterocyclyl part of the (heterocyclyl)alkyl can be further optionallysubstituted with one, two, three, four, or five groups independentlyselected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,alkyl, alkylsulfanyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, NR^(a)R^(b), and oxo.

The term “heteroarylalkoxy,” as used herein, refers to a heteroarylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heteroarylalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one heteroaryl group.

The term “heteroaryloxy,” as used herein, refers to a heteroaryl groupattached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyl,” as used herein, refers to cyclic, non-aromatic,five-, six-, or seven-membered rings containing at least one atomselected from the group consisting of oxygen, nitrogen, and sulfur. Thefive-membered rings have zero or one double bonds and the six- andseven-membered rings have zero, one, or two double bonds. Theheterocyclyl groups of the invention are connected to the parentmolecular group through a substitutable carbon or nitrogen atom in thering. The term “heterocyclyl” also includes systems where a heterocyclylring is fused to an aryl group, a cycloalkenyl group, a cycloalkylgroup, or another heterocyclyl group. Heterocyclyl groups include, butare not limited to, benzothiazolyl, dihydroindolyl, dihydropyridinyl,1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl,piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, andthiomorpholinyl. The heterocyclyl groups of the present invention can beoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl,alkylsulfonyl, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl,aryloxy, cyano, halo, haloalkoxy, haloalkyl, heteroaryl,heteroarylalkoxy, heteroarylalkyl, heteroaryloxy, a second heterocyclylgroup, (heterocyclyl)alkyl, hydroxy, hydroxyalkyl, nitro, NR^(a)R^(b),(NR^(a)R^(b))alkyl, (NR^(a)R^(b))C(O), (NR^(a)R^(b))C(O)alkyl, and oxo;wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, andthe aryloxy, the heteroaryl, the heteroaryl part of theheteroarylalkoxy, the heteroarylalkyl, and the heteroaryloxy, the secondheterocyclyl group, and the heterocyclyl part of the (heterocyclyl)alkylcan be further optionally substituted with one, two, three, four, orfive groups independently selected from the group consisting of alkenyl,alkoxy, alkoxyalkyl, alkyl, alkylsulfanyl, cyano, halo, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, nitro, NR^(a)R^(b), and oxo.

The term “(heterocyclyl)alkyl,” as used herein, refers to an alkyl groupsubstituted with at least one heterocyclyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one hydroxy group.

The term “nitro,” as used herein, refers to —NO₂.

The term “NR^(a)R^(b),” as used herein, refers to two groups, R^(a) andR^(b), which are attached to the parent molecular moiety through anitrogen atom. R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkoxycarbonylcarbonyl, aryl, arylalkyl, arylcarbonyl, cycloalkenyl,(cycloalkenyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, (NR^(c)R^(d))alkyl,(NR^(c)R^(d))C(O), and (NR^(c)R^(d))C(O)alkyl, wherein the aryl, thearyl part of the arylalkyl, and the arylcarbonyl, the heteroaryl, theheteroaryl part of the heteroarylalkyl and the heteroarylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of alkoxy, alkyl, cyano, halo, haloalkoxy, nitro, and oxo.

The term “(NR^(a)R^(b))alkyl,” as used herein, refers to an alkyl groupsubstituted with at least one NR^(a)R^(b) group.

The term “(NR^(a)R^(b))C(O),” as used herein, refers to an NR^(a)R^(b)group attached to the parent molecular moiety through a carbonyl group.

The term “(NR^(a)R^(b))C(O)alkyl,” as used herein, refers to an alkylgroup substituted with at least one (NR^(a)R^(b))C(O) group.

The term “NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, and arylalkyl; wherein the aryl and the aryl part of the arylalkylcan be further optionally substituted with one, two, three, four, orfive substituents independently selected from the group consisting ofalkoxy, alkyl, cyano, halo, haloalkoxy, nitro, and oxo.

The term “(NR^(c)R^(d))alkyl,” as used herein, refers to an alkyl groupsubstituted with at least one NR^(c)R^(d) group.

The term “(NR^(c)R^(d))C(O),” as used herein, refers to an NR^(c)R^(d)group attached to the parent molecular moiety through a carbonyl group.

The term “(NR^(c)R^(d))C(O)alkyl,” as used herein, refers to an alkylgroup substituted with at least one (NR^(c)R^(d))C(O) group.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂.

The compounds of the present invention can exist as therapeuticallyacceptable salts. The term “therapeutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent invention which are water or oil-soluble or dispersible, whichare suitable for treatment of diseases without undue toxicity,irritation, and allergic response; which are commensurate with areasonable benefit/risk ratio, and which are effective for theirintended use. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Also, suitable nitrogen atoms inthe compounds of the present invention can be quaternized with methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl,diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, andsteryl chlorides, bromides, and iodides; and benzyl and phenethylbromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The present compounds can also exist as therapeutically acceptableprodrugs. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use. The term “prodrug,” refers tocompounds which are rapidly transformed in vivo to parent compounds offormula (I) for example, by hydrolysis in blood.

In accordance with methods of treatment and pharmaceutical compositionsof the invention, the compounds can be administered alone or incombination with other anticancer agents. When using the compounds, thespecific therapeutically effective dose level for any particular patientwill depend upon factors such as the disorder being treated and theseverity of the disorder; the activity of the particular compound used;the specific composition employed; the age, body weight, general health,sex, and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the compound employed; theduration of treatment; and drugs used in combination with orcoincidently with the compound used. The compounds can be administeredorally, parenterally, osmotically (nasal sprays), rectally, vaginally,or topically in unit dosage formulations containing carriers, adjuvants,diluents, vehicles, or combinations thereof. The term “parenteral”includes infusion as well as subcutaneous, intravenous, intramuscular,and intrasternal injection.

Parenterally administered aqueous or oleaginous suspensions of thecompounds can be formulated with dispersing, wetting, or suspendingagents. The injectable preparation can also be an injectable solution orsuspension in a diluent or solvent. Among the acceptable diluents orsolvents employed are water, saline, Ringer's solution, buffers,monoglycerides, diglycerides, fatty acids such as oleic acid, and fixedoils such as monoglycerides or diglycerides.

The inhibitory effect of parenterally administered compounds can beprolonged by slowing their absorption. One way to slow the absorption ofa particular compound is administering injectable depot forms comprisingsuspensions of crystalline, amorphous, or otherwise water-insolubleforms of the compound. The rate of absorption of the compound isdependent on its rate of dissolution which is, in turn, dependent on itsphysical state. Another way to slow absorption of a particular compoundis administering injectable depot forms comprising the compound as anoleaginous solution or suspension. Yet another way to slow absorption ofa particular compound is administering injectable depot forms comprisingmicrocapsule matrices of the compound trapped within liposomes,microemulsions, or biodegradable polymers such aspolylactide-polyglycolide, polyorthoesters or polyanhydrides. Dependingon the ratio of drug to polymer and the composition of the polymer, therate of drug release can be controlled.

Transdermal patches can also provide controlled delivery of thecompounds. The rate of absorption can be slowed by using ratecontrolling membranes or by trapping the compound within a polymermatrix or gel. Conversely, absorption enhancers can be used to increaseabsorption.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In these solid dosage forms, the activecompound can optionally comprise diluents such as sucrose, lactose,starch, talc, silicic acid, aluminum hydroxide, calcium silicates,polyamide powder, tableting lubricants, and tableting aids such asmagnesium stearate or microcrystalline cellulose. Capsules, tablets andpills can also comprise buffering agents, and tablets and pills can beprepared with enteric coatings or other release-controlling coatings.Powders and sprays can also contain excipients such as talc, silicicacid, aluminum hydroxide, calcium silicate, polyamide powder, ormixtures thereof. Sprays can additionally contain customary propellantssuch as chlorofluorohydrocarbons or substitutes therefore.

Liquid dosage forms for oral administration include emulsions,microemulsions, solutions, suspensions, syrups, and elixirs comprisinginert diluents such as water. These compositions can also compriseadjuvants such as wetting, emulsifying, suspending, sweetening,flavoring, and perfuming agents.

Topical dosage forms include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and transdermal patches. Thecompound is mixed under sterile conditions with a carrier and any neededpreservatives or buffers. These dosage forms can also include excipientssuch as animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.Suppositories for rectal or vaginal administration can be prepared bymixing the compounds with a suitable non-irritating excipient such ascocoa butter or polyethylene glycol, each of which is solid at ordinarytemperature but fluid in the rectum or vagina. Ophthalmic formulationscomprising eye drops, eye ointments, powders, and solutions are alsocontemplated as being within the scope of this invention.

The total daily dose of the compounds administered to a host in singleor divided doses can be in amounts from about 0.1 to about 200 mg/kgbody weight or preferably from about 0.25 to about 100 mg/kg bodyweight. Single dose compositions can contain these amounts orsubmultiples thereof to make up the daily dose.

Preferred compounds of the present invention are compounds of formula(I) where R² is -LR⁸; L is —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—; R⁹ and R¹⁰are hydrogen; and m is 0.

Determination of Biological Activity

The in vitro potency of compounds in inhibiting these protein kinasesmay be determined by the procedures detailed below.

The potency of compounds can be determined by the amount of inhibitionof the phosphorylation of an exogenous substrate (e.g., syntheticpeptide (Z. Songyang et al., Nature. 373:536-539) by a test compoundrelative to control.

KDR Tyrosine Kinase Production Using Baculovirus System:

The coding sequence for the human KDR intra-cellular domain (aa789-1354)was generated through PCR using cDNAs isolated from HUVEC cells. Apoly-His6 sequence was introduced at the N-terminus of this protein aswell. This fragment was cloned into transfection vector pVL1393 at theXba 1 and Not 1 site. Recombinant baculovirus (BV) was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 cells were grown in SF-900-IImedium at 2×106/mL, and were infected at 0.5 plaque forming units percell (MOI). Cells were harvested at 48 hours post infection.

Purification of KDR

SF-9 cells expressing (His)₆ KDR(aa789-1354) were lysed by adding 50 mLof Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10%glycerol, 1% Triton X-100, 1 mM PMSF, 10 μg/mL aprotinin, 1 μg/mLleupeptin) to the cell pellet from 1 L of cell culture. The lysate wascentrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 minutes at 4°C. The cell lysate was applied to a 5 mL NiCl₂ chelating sepharosecolumn, equilibrated with 50 mM HEPES, pH7.5, 0.3M NaCl. KDR was elutedusing the same buffer containing 0.25M imidazole. Column fractions wereanalyzed using SDS-PAGE and an ELISA assay (below) which measures kinaseactivity. The purified KDR was exchanged into 25 mM HEPES, pH7.5, 25 mMNaCl, 5 mM DTT buffer and stored at −80° C.

Compounds of the present invention inhibited KDR at IC50's between about0.003 μM and >50 μM. Preferred compounds inhibited KDR at IC50's betweenabout 0.003 μM and about 0.5 μM.

Human Tie-2 Kinase Production and Purification

The coding sequence for the human Tie-2 intra-cellular domain(aa775-1124) was generated through PCR using cDNAs isolated from humanplacenta as a template. A poly-His₆ sequence was introduced at theN-terminus and this construct was cloned into transfection vector pVL1939 at the Xba 1 and Not 1 site. Recombinant BV was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 insect cells were grown inSF-900-II medium at 2×106/mL, and were infected at MOI of 0.5.Purification of the His-tagged kinase used in screening was analogous tothat described for KDR.

Compounds of the present invention inhibited Tie-2 at IC50's betweenabout 0.01 μM and >50 μM. Preferred compounds inhibited Tie-2 at IC50'sbetween about 0.01 μM and 0.5 μM.

Human Flt-1 Tyrosine Kinase Production and Purification

The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles,Calif.) was used. A nucleotide sequence encoding poly-His6 was placed 5′to the nucleotide region encoding the entire intracellular kinase domainof human Flt-1 (amino acids 786-1338). The nucleotide sequence encodingthe kinase domain was generated through PCR using cDNA librariesisolated from HUVEC cells. The histidine residues enabled affinitypurification of the protein as a manner analogous to that for KDR andZAP70. SF-9 insect cells were infected at a 0.5 multiplicity andharvested 48 hours post infection.

EGFR Tyrosine Kinase Source

EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 μl) and theEGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat# PF011-100).

Expression of ZAP70

The baculoviral expression vector used was pVL1393. (Pharmingen, LosAngeles, Calif.) The nucleotide sequence encoding amino acids M(H)6LVPR₉S was placed 5′ to the region encoding the entirety of ZAP70 (aminoacids 1-619). The nucleotide sequence encoding the ZAP70 coding regionwas generated through PCR using cDNA libraries isolated from Jurkatimmortalized T-cells. The histidine residues enabled affinitypurification of the protein (vide infra). The LVPR₉S bridge constitutesa recognition sequence for proteolytic cleavage by thrombin, enablingremoval of the affinity tag from the enzyme. SF-9 insect cells wereinfected at a multiplicity of infection of 0.5 and harvested 48 hourspost infection.

Extraction and Purification of ZAP70

SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg/mL leupeptin, 10μg/mL aprotinin and 1 mM sodium orthovanadate. The soluble lysate wasapplied to a chelating sepharose HiTrap column (Pharmacia) equilibratedin 50 mM HEPES, pH 7.5, 0.3M NaCl. Fusion protein was eluted with 250 mMimidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH7.5, 50 mM NaCl and 5 mM DTT.

Protein Kinase Source

Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may becommercially obtained (e.g., from Upstate Biotechnology Inc. (SaranacLake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) orpurified from known natural or recombinant sources using conventionalmethods.

Enzyme Linked Immunosorbent Assay (ELISA) for PTKs

Enzyme linked immunosorbent assays (ELISA) were used to detect andmeasure the presence of tyrosine kinase activity. The ELISA wereconducted according to known protocols which are described in, forexample, Voller, et al., 1980, “Enzyme-Linked Immunosorbent Assay,” In:Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp359-371 Am. Soc. of Microbiology, Washington, D.C.

The disclosed protocol was adapted for determining activity with respectto a specific PTK. For example, preferred protocols for conducting theELISA experiments is provided below. Adaptation of these protocols fordetermining a compound's activity for other members of the receptor PTKfamily, as well as non-receptor tyrosine kinases, are well within theabilities of those in the art. For purposes of determining inhibitorselectivity, a universal PTK substrate (e.g., random copolymer ofpoly(Glu₄ Tyr), 20,000-50,000 MW) was employed together with ATP(typically 5 μM) at concentrations approximately twice the apparent Kmin the assay.

The following procedure was used to assay the inhibitory effect ofcompounds of this invention on KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR,FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn, fgr, Fyn andZAP70 tyrosine kinase activity:

Buffers and Solutions:

PGTPoly (Glu, Tyr) 4:1

Store powder at −20° C. Dissolve powder in phosphate buffered saline(PBS) for 50 mg/mL solution. Store 1 mL aliquots at −20° C. When makingplates dilute to 250 μg/mL in Gibco PBS.

Reaction Buffer: 100 mM Hepes, 20 mM MgCl₂, 4 mM MnCl₂, 5 mM DTT, 0.02%BSA, 200 μM NaVO₄, pH 7.10

ATP: Store aliquots of 100 mM at −20° C. Dilute to 20 μM in water

Washing Buffer: PBS with 0.1% Tween 20

Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS

TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just beforeuse or use K-Blue Substrate from Neogen

Stop Solution: 1M Phosphoric Acid

Procedure

1. Plate Preparation:

Dilute PGT stock (50 mg/mL, frozen) in PBS to a 250 μg/mL. Add 125 μLper well of Corning modified flat bottom high affinity ELISA plates(Corning #25805-96). Add 125 μL PBS to blank wells. Cover with sealingtape and incubate overnight 37° C. Wash 1× with 250 μL washing bufferand dry for about 2 hours in 37° C. dry incubator.

Store coated plates in sealed bag at 4° C. until used.

2. Tyrosine Kinase Reaction:

-   -   Prepare inhibitor solutions at a 4× concentration in 20% DMSO in        water.    -   Prepare reaction buffer    -   Prepare enzyme solution so that desired units are in 50 μL, e.g.        for KDR make to 1 ng/μL for a total of 50 ng per well in the        reactions. Store on ice    -   Make 4×ATP solution to 2 μM from 100 mM stock in water. Store on        ice    -   Add 50 μL of the enzyme solution per well (typically 5-50 ng        enzyme/well depending on the specific activity of the kinase)    -   Add 25 μL 4× inhibitor    -   Add 25 μL 4×ATP for inhibitor assay    -   Incubate for 10 minutes at room temperature    -   Stop reaction by adding 50 μL 0.05N HCl per well    -   Wash plate        **Final Concentrations for Reaction: 5 μM ATP, 5% DMSO        3. Antibody Binding    -   Dilute 1 mg/mL aliquot of PY20-HRP (Pierce) antibody (a        phosphotyrosine antibody) to 50 ng/mL in 0.1% BSA in PBS by a 2        step dilution (100×, then 200×)    -   Add 100 μL Ab per well. Incubate 1 hour at room temperature.        Incubate 1 hour at 4° C.    -   Wash 4× plate        4. Color reaction    -   Prepare TMB substrate and add 100 μL per well    -   Monitor OD at 650 nm until 0.6 is reached    -   Stop with 1M phosphoric acid. Shake on plate reader.    -   Read OD immediately at 450 nm

Optimal incubation times and enzyme reaction conditions vary slightlywith enzyme preparations and are determined empirically for each lot.

For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mMMnCl₂, 20 mM MgCl₂, 5 mM DTT, 0.2% BSA, 200 mM NaVO₄ under the analogousassay conditions.

Cdc2 Source

The human recombinant enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly, Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Cdc2 Assay

A protocol that can be used is that provided with the purchased reagentswith minor modifications. In brief, the reaction is carried out in abuffer consisting of 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mMDTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂ (commercial buffer)supplemented with fresh 300 μM ATP (31 μCi/mL) and 30 μg/mL histone typeIIIss final concentrations. A reaction volume of 80 μL, containing unitsof enzyme, is run for 20 minutes at 25 degrees C. in the presence orabsence of inhibitor. The reaction is terminated by the addition of 120μL of 10% acetic acid. The substrate is separated from unincorporatedlabel by spotting the mixture on phosphocellulose paper, followed by 3washes of 5 minutes each with 75 mM phosphoric acid. Counts are measuredby a betacounter in the presence of liquid scintillant.

PKC Kinase Source

The catalytic subunit of PKC may be obtained commercially (Calbiochem).

PKC Kinase Assay

A radioactive kinase assay is employed following a published procedure(Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A.,Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166,1220-1227 (1990)). Briefly, all reactions are performed in a kinasebuffer consisting of 50 mM Tris-HCl pH7.5, 10 mM MgCl₂, 2 mM DTT, 1 mMEGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³P ATP (8 Ci/mM). Compoundand enzyme are mixed in the reaction vessel and the reaction isinitiated by addition of the ATP and substrate mixture. Followingtermination of the reaction by the addition of 10 μL stop buffer (5 mMATP in 75 mM phosphoric acid), a portion of the mixture is spotted onphosphocellulose filters. The spotted samples are washed 3 times in 75mM phosphoric acid at room temperature for 5 to 15 minutes.Incorporation of radiolabel is quantified by liquid scintillationcounting.

Erk2 Enzyme Source

The recombinant murine enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Erk2 Enzyme Assay

In brief, the reaction is carried out in a buffer consisting of 50 mMTris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂(commercial buffer) supplemented with fresh 100 μM ATP (31 μCi/mL) and30 μM myelin basic protein under conditions recommended by the supplier.Reaction volumes and method of assaying incorporated radioactivity areas described for the PKC assay (vide supra).

Cellular Receptor PTK Assays

The following cellular assay was used to determine the level of activityand effect of the different compounds of the present invention onKDR/VEGFR2. Similar receptor PTK assays employing a specific ligandstimulus can be designed along the same lines for other tyrosine kinasesusing techniques well known in the art.

VEGF-Induced KDR Phosphorylation in Human Umbilical Vein EndothelialCells (HUVEC) as Measured by Western Blots:

1. HUVEC cells (from pooled donors) can be purchased from Clonetics (SanDiego, Calif.) and cultured according to the manufacturer directions.Only early passages (3-8) are used for this assay. Cells are cultured in100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth,England) using complete EBM media (Clonetics).

2. For evaluating a compound's inhibitory activity, cells aretrypsinized and seeded at 0.5-1.0×10⁵ cells/well in each well of 6-wellcluster plates (Costar; Cambridge, Mass.).

3. 3-4 days after seeding, plates are typically 90-100% confluent.Medium is removed from all the wells, cells are rinsed with 5-10 mL ofPBS and incubated 18-24 h with 5 mL of EBM base media with nosupplements added (i.e., serum starvation).

4. Serial dilutions of inhibitors are added in 1 mL of EBM media (25 μM,5 μM, or 1 μM final concentration to cells and incubated for one hour at37° C. Human recombinant VEGF₁₆₅ (R & D Systems) is then added to allthe wells in 2 mL of EBM medium at a final concentration of 50 ng/mL andincubated at 37° C. for 10 minutes. Control cells untreated or treatedwith VEGF only are used to assess background phosphorylation andphosphorylation induction by VEGF.

All wells are then rinsed with 5-10 mL of cold PBS containing 1 mMSodium Orthovanadate (Sigma) and cells are lysed and scraped in 200 μLof RIPA buffer (50 mM Tris-HCl) pH 7, 150 mM NaCl, 1% NP-40, 0.25%sodium deoxycholate, 1 mM EDTA) containing protease inhibitors (PMSF 1mM, aprotinin 1 μg/mL, pepstatin 1 μg/mL, leupeptin 1 μg/mL, Na vanadate1 mM, Na fluoride 1 mM) and 1 μg/mL of Dnase (all chemicals from SigmaChemical Company, St Louis, Mo.). The lysate is spun at 14,000 rpm for30 minutes, to eliminate nuclei.

Equal amounts of proteins are then precipitated by addition of cold(−20° C.) ethanol (2 volumes) for a minimum of 1 hour or a maximum ofovernight. Pellets are reconstituted in LaemLi sample buffer containing5%-mercaptoethanol (BioRad; Hercules, Calif.) and boiled for 5 minutes.The proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, Calif.) and transferred onto a nitrocellulosemembrane using the Novex system. After blocking with bovine serumalbumin (3%), the proteins are probed overnight with anti-KDR polyclonalantibody (C20, Santa Cruz Biotechnology; Santa Cruz, Calif.) or withanti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology,Lake Placid, N.Y.) at 4° C. After washing and incubating for 1 hour withHRP-conjugated F(ab)₂ of goat anti-rabbit or goat-anti-mouse IgG thebands are visualized using the emission chemiluminescience (ECL) system(Amersham Life Sciences, Arlington Heights, Ill.).

In Vivo Uterine Edema Model

This assay measures the capacity of compounds to inhibit the acuteincrease in uterine weight in mice which occurs in the first few hoursfollowing estrogen stimulation. This early onset of uterine weightincrease is known to be due to edema caused by increased permeability ofuterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993),133:829-837) demonstrated a close temporal relationship ofestrogen-stimulated uterine edema with increased expression of VEGF mRNAin the uterus. These results have been confirmed by the use ofneutralizing monoclonal antibody to VEGF which significantly reduced theacute increase in uterine weight following estrogen stimulation (WO97/42187). Hence, this system can serve as a model for in vivoinhibition of VEGF signalling and the associated hyperpermeability andedema.

Materials: All hormones can be purchased from Sigma (St. Louis, Mo.) orCal Biochem (La Jolla, Calif.) as lyophilized powders and preparedaccording to supplier instructions. Vehicle components (DMSO, CremaphorEL) can be purchased from Sigma (St. Louis, Mo.). Mice (Balb/c, 8-12weeks old) can be purchased from Taconic (Germantown, N.Y.) and housedin a pathogen-free animal facility in accordance with institutionalAnimal Care and Use Committee Guidelines.

Method:

Day 1: Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5units of pregnant mare's serum gonadotropin (PMSG).

Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.

Day 4: Mice are randomized and divided into groups of 5-10. Testcompounds are administered by i.p., i.v. or p.o. routes depending onsolubility and vehicle at doses ranging from 1-100 mg/kg. Vehiclecontrol group receive vehicle only and two groups are left untreated.

Thirty minutes later, experimental, vehicle and 1 of the untreatedgroups are given an i.p. injection of 17-estradiol (500 mg/kg). After2-3 hours, the animals are sacrificed by CO₂ inhalation. Following amidline incision, each uterus was isolated and removed by cutting justbelow the cervix and at the junctions of the uterus and oviducts. Fatand connective tissue were removed with care not to disturb theintegrity of the uterus prior to weighing (wet weight). Uteri areblotted to remove fluid by pressing between two sheets of filter paperwith a one liter glass bottle filled with water. Uteri are weighedfollowing blotting (blotted weight). The difference between wet andblotted weights is taken as the fluid content of the uterus. Mean fluidcontent of treated groups is compared to untreated or vehicle treatedgroups. Significance is determined by Student's test. Non-stimulatedcontrol group is used to monitor estradiol response.

Certain compounds of this invention which are inhibitors of angiogenicreceptor tyrosine kinases can also be shown active in a Matrigel implantmodel of neovascularization. The Matrigel neovascularization modelinvolves the formation of new blood vessels within a clear marble ofextracellular matrix implanted subcutaneously which is induced by thepresence of proangiogenic factor producing tumor cells (for examplessee: Passaniti, A., et al., Lab. Investig. (1992), 67(4), 519-528; Anat.Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vasc.Biol. (1995), 15(11), 1857-6). The model preferably runs over 3-4 daysand endpoints include macroscopic visual/image scoring ofneovascularization, microscopic microvessel density determinations, andhemoglobin quantitation (Drabkin method) following removal of theimplant versus controls from animals untreated with inhibitors. Themodel may alternatively employ bFGF or HGF as the stimulus.

The compounds of the present invention may be used in the treatment ofprotein kinase-mediated conditions, such as benign and neoplasticproliferative diseases and disorders of the immune system. Such diseasesinclude autoimmune diseases, such as rheumatoid arthritis, thyroiditis,type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory boweldisease, Crohn's disease, myasthenia gravis and systemic lupuserythematosus; psoriasis, organ transplant rejection (e.g., kidneyrejection, graft versus host disease), benign and neoplasticproliferative diseases, human cancers such as lung, breast, stomach,bladder, colon, pancreatic, ovarian, prostate and rectal cancer andhematopoietic malignancies (leukemia and lymphoma), glioblastoma,infantile hemangioma, and diseases involving inappropriatevascularization (for example diabetic retinopathy, retinopathy ofprematurity, choroidal neovascularization due to age-related maculardegeneration, and infantile hemangiomas in human beings). Suchinhibitors may be useful in the treatment of disorders involving VEGFmediated edema, ascites, effusions, and exudates, including for examplemacular edema, cerebral edema, acute lung injury and adult respiratorydistress syndrome (ARDS). In addition, the compounds of the inventionmay be useful in the treatment of pulmonary hypertension, particularlyin patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg.2001, 122 (1), 65-73).

Compounds of the invention may have therapeutic utility in the treatmentof diseases involving both identified, including those not mentionedherein, and as yet unidentified protein tyrosine kinases. Preferredcompounds of the invention are compounds which have shown the ability toinhibit multiple kinases and may not necessarily be the most potentinhibitors of any one particular kinase.

Synthetic Methods

Abbreviations which have been used in the descriptions of the scheme andthe examples that follow are: THF for tetrahydrofuran; NBS forN-bromosuccinimide; AIBN for 2,2′-azobisisobutyronitrile; DMF forN,N-dimethylformamide; NMP for 1-methyl-2-pyrrolidinone; EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCC for1,3-dicyclohexylcarbodiimide; HOBT for 1-hydroxybenzotriazole; PPh₃ fortriphenylphosphine; DMSO for dimethylsulfoxide; NMM forN-methylmorpholine; and TBAF for tetrabutylammonium fluoride.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups R³, R⁸, R⁹, R¹⁰, X, Z¹, Z², Z³,Z⁴, and m are as defined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Scheme 1 shows the synthesis of compounds of formula (6). Compounds offormula (2) can be converted to compounds of formula (3) by treatmentwith malonitrile, ammonium acetate, and acetic acid. The reaction istypically conducted in benzene under azeotropic conditions attemperatures of about 80° C. to about 90° C. Reactions times are about12 to about 96 hours.

Compounds of formula (4) can be formed from compounds of formula (3) bytreatment with a base such as triethylamine, diethylamine, ordiisopropylethylamine and sulfur. Examples of solvents used in thesereactions include ethanol, methanol, and isopropanol. The reaction istypically conducted at about 25° C. to about 80° C. for about 1 to about6 hours.

Conversion of compounds of formula (4) to compounds of formula (5) canbe accomplished by treatment with formamide. The reaction is typicallyrun neat at temperatures of about 150° C. to about 160° C. for about 8to about 24 hours or in a microwave oven at temperatures of about 180°C. to about 250° C. for about 5 minutes to about 90 minutes.

Compounds of formula (4) can also be converted to compounds of formula(5) by treatment with ammonium sulfate in triethylorthoformate followedby treatment with ammonia. The reaction is typically conducted attemperatures between about 20° C. and about 180° C. for about 4 to about12 hours.

Compounds of formula (5) can be converted to compounds of formula (6) bytreatment with a reducing agent. Representative reducing agents includeiron powder and ammonium chloride, iron powder and HCl, tin and HCl, andzinc and HCl. Examples of solvents used in these reactions includeethanol, THF, water, methanol, and mixtures thereof. The reaction istypically conducted at about 60° C. to about 85° C. and reaction timesare about 1 to about 4 hours.

An alternative synthesis of compounds of formula (6) is shown in Scheme2. Compounds of formula (7) (prepared according to the proceduresdescribed in Scheme 1), can be converted to compounds of formula (8) byradical bromination with NBS and AIBN. Representative solvents used inthese reactions include benzene and THF. The reaction is typicallyconducted at about 70° C. to about 80° C. for about 2 to about 6 hours.

Compounds of formula (8) can be treated with a nucleophile such as aheterocyclyl group, an amine, or an alkoxy group to provide compounds offormula (5) where R³ is alkoxyalkyl, (NR^(a)R^(b))alkyl, or(heterocyclyl)alkyl. Representative solvents used in these reactionsinclude DMF, NMP, and dioxane. The reaction is typically conducted atabout 20° C. to about 35° C. for about 12 to about 24 hours.

Conversion of compounds of formula (5) to compounds of formula (6) canbe accomplished by treatment with a reducing agent as described inScheme 1.

The synthesis of compounds of formula (9) (compounds of formula (I)where R² is -LR⁸ and L is —(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—) is shown inScheme 3. Compounds of formula (6) can be converted to compounds offormula (9) by treatment with an appropriately substituted isocyanate(R¹⁰N(R⁸)C(O)). Examples of solvents used in these reactions includedichloromethane, chloroform, and carbon tetrachloride, and DMF. Thereaction is typically conducted at about −10° C. to about 25° C. forabout 12 to about 24 hours.

Alternatively, compounds of formula (6) can be reacted with an acylatingagent such as p-nitrophenyl chloroformate then treated with anappropriately substituted amine (HNR¹⁰R⁸) in the presence of a base suchas triethylamine, diisopropylethylamine, or pyridine to providecompounds of formula (9). The reaction is typically conducted in asolvent such as THF, methyl tert-butyl ether, or diethyl ether. Thereaction is commonly run at temperatures between −5° C. and 35° C. forbetween about 1 hour and 24 hours.

Scheme 4 shows the synthesis of compounds of formula (10) (compounds offormula (I) where R² is -LR⁸ and L is —NR⁹SO₂—). Compounds of formula(6) can be treated with an appropriately substituted sulfonyl chloride(R⁸SO₂Cl) and a base such as pyridine or triethylamine. Representativesolvents used in these reactions include dichloromethane, carbontetrachloride, and chloroform. The reaction is typically conducted atabout −10° C. to about 20° C. for about 12 to about 24 hours.

As shown in Scheme 5, compounds of formula (6) can be converted tocompounds of formula (11) (R⁵ is selected from the group of substituentslisted in the definition of heteroaryl; a is 0, 1, 2, 3, or 4; these arecompounds of formula (I) where R² is -LR⁸; L is —NR⁹—; and R⁸ isheteroaryl) by treatment with 1,1-thiocarbonyldiimidazole in thepresence of pyridine and an optionally substituted 2-aminophenol;followed by treatment with a coupling agent such as EDC or DCC. Thereaction is typically conducted at about −5° C. to about 65° C. forabout 32 to about 48 hours.

As shown in Scheme 6, compounds of formula (6) can be converted tocompounds of formula (12) (compounds of formula (I) where R² is -LR⁸; Lis —NR^(c)—; and R⁸ is heteroaryl) by treatment with a heteroaryl groupsubstituted by a leaving group such as a chloride or a fluoride.Typically the reaction is run neat at temperatures of about 150° C. toabout 210° C. Reaction times are about 10 minutes to about 24 hours.

Scheme 7 shows the synthesis of compounds of formula (13) (compounds offormula (I) where R² is -LR⁸ and L is —NR^(c)C(O)—). Compounds offormula (6) can be treated with an appropriately substituted acidchloride (R⁸C(O)Cl) and a base such as pyridine, triethylamine, ordiisopropylethylamine. Representative solvents used in these reactionsinclude dichloromethane, chloroform, and diethyl ether. The reaction istypically conducted at about −5° C. to about 30° C. for about 2 to about24 hours.

Compounds of formula (16) (compounds of formula (I) where R² is -LR⁸ andL is —C(O)NR⁹—) can be prepared as described in Scheme 8. Compounds offormula (14) (which can be prepared by substituting the corresponding4-bromophenyl ketone for the compound of formula (2) in the synthesis ofcompounds of formula (5) described in Scheme 1) can be treated with analkyllithium such as n-butyllithium or t-butyllithium and dry ice toprovide compounds of formula (15). Representative solvents used in thesereactions include hexanes, THF and heptane. The reaction is typicallyconducted at about −80° C. to about 0° C. for about 30 minutes to about2 hours.

Conversion of compounds of formula (15) to compounds of formula (16) canbe accomplished by treatment with an appropriately substituted amine(HNR⁹R⁸) in the presence of agents such as HOBT and EDC or DCC or1,1′-carbonyldiimidazole in the presence of a base such asN-methylmorpholine. Examples of solvents used in these reactions includeDMF and NMP. The reaction is typically conducted at about 20° C. toabout 35° C. for about 12 to about 24 hours.

Scheme 9 shows the synthesis of compounds of formula (22) (compounds offormula (I) where X is N and R² is NO₂). Compounds of formula (17) canbe treated with PCl₅ to provide compounds of formula (18).Representative solvents include dichloromethane, chloroform, and carbontetrachloride. The reaction is typically run at about 25° C. to about40° C. for about 10 to about 30 hours.

Conversion of compounds of formula (18) to compounds of formula (19) canbe accomplished by treatment with ammonium hydroxide to providecompounds of formula (19). Examples of solvents include ethanol andmethanol. The reaction is typically conducted at about 20° C. to about30° C. for about 2 to about 6 hours.

Compounds of formula (19) can be converted to compounds of formula (20)by treatment with diethyl dithiophosphate. Representative solventsinclude ethanol and methanol. The reaction is typically conducted atabout 70° C. to about 80° C. for about 12 to about 36 hours.

Conversion of compounds of formula (20) to compounds of formula (21) canbe accomplished by treatment with hydrogen peroxide. Representativesolvents used in these reactions include ethanol and methanol. Thereaction is typically conducted at about 20° C. to about 30° C. forabout 12 to about 24 hours.

Compounds of formula (21) can be converted to compounds of formula (22)following the procedures described in Scheme 1. Upon reducing the nitrogroup to an amine following the procedures in Scheme 1, these compoundscan be further modified to provide compounds similar in structure tothose shown in Schemes 3 through 8.

Scheme 10 shows the synthesis of compounds of formula (25) (compounds offormula (I) where R¹ is NH₂). Compounds of formula (23) (preparedaccording to the methods described in Schemes 1, 2, or 9) can beconverted to compounds of formula (24) by treatment withchloroformamidine in diglyme. The reaction is typically conducted attemperatures of between about 120 and 140° C. for about 12 to about 18hours.

Compounds of formula (24) can be converted to compounds of formula (25)using the procedures described in the previous schemes.

The present invention will now be described in connection with certainpreferred embodiments which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purposes of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 5.0(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names which appeared to be consistent with ACDnomenclature.

EXAMPLE 1N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-phenylureaEXAMPLE 1A 1-(4-nitrophenyl)propan-1-one

A solution of 0.5M ZnCl₂ in THF (60 mL, 30 mmol) in THF (20 mL) wastreated with 2M ethyl magnesium chloride in THF (15 mL, 30 mmol)dropwise by syringe, cooled with an ice bath for about 10 minutes,stirred at room temperature for about 20 minutes, cooled to 0° C., andtreated sequentially with Pd(PPh₃)₄ (1.73 g, 1.5 mmol) and a solution of4-nitrobenzoyl chloride (6.12 g, 33 mmol) in THF (20 mL). The mixturewas stirred at 0° C. for 40 minutes, diluted with water, adjusted to pH1 with 2N HCl and extracted three times with ethyl acetate. The combinedextracts were washed sequentially with saturated Na₂CO₃, water, andbrine, dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 6:1hexanes/ethyl acetate to provide 2.17 g (40%) of the desired product asa yellow solid. R_(f)=0.6 (3:1 hexanes/ethyl acetate).

EXAMPLE 1B 2-[1-(4-nitrophenyl)propylidene]malononitrile

A solution of Example 1A (3.4 g, 19 mmol), malononitrile (1.25 g, 19mmol) ammonium acetate (1.46 g) and acetic acid (2 mL) in benzene (50mL) was heated to reflux in a flask fitted with a Dean-Stark trap for 14hours. Additional ammonium acetate (1.46 g) and acetic acid (2 mL) wereadded and the reaction was stirred at reflux for 4 more hours. Themixture was cooled to room temperature and partitioned between water andethyl acetate. The aqueous layer was extracted twice with ethyl acetateand the combined extracts were washed with brine, dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 3:1 hexanes/ethyl acetate to provide4.01 g (93%) of the desired product as a yellow solid. R_(f)=0.45 (3:1hexanes/ethyl acetate).

EXAMPLE 1C 2-amino-5-methyl-4-(4-nitrophenyl)thiophene-3-carbonitrile

Diethylamine (1.57 mL) was added dropwise to a suspension of Example 1B(4.0 g, 17.6 mmol) and sulfur (0.563 g, 17.6 mmol) in ethanol (60 mL).The mixture was heated to 70° C. for 2 hours, cooled to roomtemperature, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 3:2 hexanes/ethyl acetate toprovide 4.05 g (89%) of the desired product. MS (CI) m/e 277 (M+NH₄)⁺.

EXAMPLE 1D 6-methyl-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 1C (4.03 g, 15.5 mmol) in formamide (60 mL) wasstirred at 155° C. for 17 hours, cooled to room temperature, dilutedwith water, and filtered. The filter cake was dried to provide 4.126 g(93%) of the desired product. MS (CI) m/e 287 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.36 (d, J=9.0 Hz, 2H); 8.30 (s, 1H); 7.68 (d, J=9.0 Hz, 2H);2.32 (s, 3H); Anal. Calcd. for C₁₃H₁₀N₄O₂S: C, 54.53; H, 3.52; N, 19.57.Found: C, 54.75; H, 3.39; N, 19.17.

EXAMPLE 1E 5-(4-aminophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

A suspension of Example 1D (1.01 g, 3.53 mmol) in ethanol (60 mL), THF(20 mL), and water (10 mL) was treated with NH₄Cl (0.19 g, 3.53 mmol)and iron powder (1.18 g, 21.2 mmol), and stirred at 70-80° C. for 1hour. The mixture was diluted with ethanol (40 mL) and filtered througha pad of diatomaceous earth (Celite®) while still hot. The pad waswashed with ethanol and the filtrate was concentrated. The concentratewas diluted with water and extracted three times with ethyl acetate. Thecombined extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated to provide 1 g of the desired product. MS (CI) m/e 257(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H); 7.01 (d, J=8.4 Hz,2H); 6.70 (d, J=8.4 Hz, 2H); 5.39 (s, 2H); 2.27 (s, 3H); Anal. Calcd.for C₁₃H₁₂N₄S.0.2C₄H₈O₂.0.2H₂O: C, 59.72; H, 5.08; N, 20.19. Found:59.64; H, 4.99; N, 20.22.

EXAMPLE 1FN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-phenylurea

A 0° C. solution of Example 1E (80 mg, 0.3 mmol) in dichloromethane (4mL) was treated with phenyl isocyanate (0.037 mL, 0.34 mmol), stirredovernight, and filtered. The filter cake was dried to provide 0.103 g(87%) of the desired product. MS (CI) m/e 376 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.89 (s, 1H); 8.75 (s, 1H); 8.26 (s, 1H); 7.63 (d, J=8.7 Hz,2H); 7.47 (d, J=8.7 Hz, 2H); 7.33-7.26 (m, 4H); 6.99 (t, J=7.5 Hz, 1H);2.30 (s, 3H); Anal. Calcd. for C₂₀H₁₇N₅OS.0.1CH₂Cl₂: C, 62.88; H, 4.52;N, 18.24. Found: C, 62.85; H, 4.64; N, 18.15.

EXAMPLE 2N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzenesulfonamide

A 0° C. solution of Example 1E (0.1 g, 0.39 mmol) in dichloromethane (4mL) was treated with pyridine (0.038 mL, 0.47 mmol) and benzenesulfonylchloride (0.05 mL, 0.4 mmol), stirred at 0° C. for 1 hour, then stirredat room temperature overnight. The reaction mixture was diluted withwater and extracted twice with dichloromethane. The combined extractswere washed with brine, dried (MgSO₄), filtered, and concentrated. Theconcentrate was triturated from dichloromethane/hexanes to provide 91 mg(59%) of the desired product. MS(ESI(+)) m/e 397 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 10.49 (s, 1H); 8.25 (s, 1H); 7.77 (m, 2H); 7.65-7.55 (m,3H); 7.24 (m, 4H); 1.99 (s, 3H); Anal. Calcd. for C₁₉H₁₆N₄O₂S₂0.3C₂H₄O₂:C, 57.37; H, 4.39; N, 13.25. Found: C, 57.22; H, 4.48; N, 13.32.

EXAMPLE 35-[4-(1,3-benzoxazol-2-ylamino)phenyl]-6-methylthieno[2,3-d]pyrimidin-4-amine

A solution of Example 1E (100 mg, 0.39 mmol) in pyridine (3 mL) wasadded dropwise over 5 minutes to a 0° C. solution of1,1-thiocarbonyldiimidazole (77 mg, 0.39 mmol) in pyridine (3 mL). Thereaction was stirred at 0° C. for 1.5 hours, then treated with2-aminophenol (43 mg, 0.39 mmol), stirred overnight at room temperature,treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(90 mg, 0.47 mmol), and heated to 50° C. for 20 hours. The mixture wasconcentrated and the residue was partitioned between ethyl acetate andwater. The aqueous phase was extracted twice with ethyl acetate and thecombined extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with ethyl acetate to provide 28 mg (20%)of the desired product. MS (CI) m/e 374 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 10.89 (s, 1H); 8.27 (s, 1H); 7.94 (d, J=8.4 Hz, 2H); 7.51 (m,2H); 7.42 (d, J=8.4 Hz, 2H); 7.25 (td, J=7.5 Hz, 1.5 Hz, 1H); 7.16 (td,J=7.5 Hz, 1.5 Hz, 1H); 3.10 (s, 3H); Anal. Calcd. forC₂₀H₁₅N₅OS.0.2C₄H₈O₂.0.2H₂O: C, 63.30; H, 4.34; N, 17.75. Found: C,63.52; H, 4.30; N, 17.33.

EXAMPLE 4N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzamide

A 0° C. solution of Example 1E (80 mg, 0.31 mmol) in dichloromethane (4mL) was treated with pyridine (0.03 mL, 0.38 mmol) and benzoyl chloride(0.038 mL, 0.32 mmol), stirred at 0° C. for 1 hour, then at roomtemperature overnight. The reaction mixture was diluted with water andextracted twice with dichloromethane. The combined extracts were washedwith brine, dried (MgSO₄), filtered, and concentrated. The concentratewas purified by flash column chromatography on silica gel with ethylacetate to provide 39 mg (35%) of the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 10.46 (s, 1H); 8.28 (s, 1H); 7.98 (d, J=8.1 Hz, 4H);7.63-7.54 (m, 3H); 7.40 (d, J=8.1 Hz, 2H); 2.31 (s, 3H); HRMS(ESI)Calcd. for C₂₀H₁₇N₄O_(S): 361.1118. Found: 36.1122.

EXAMPLE 5N-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methylphenyl)ureaEXAMPLE 5A 6-isopropyl-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting isobutyl magnesiumbromide for ethyl magnesium bromide in Examples 1A-1D. m.p. >260° C.;MS(ESI(+)) m/e 315 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.22 (d,J=6.9 Hz, 6H); 2.94-3.03 (m, 1H); 7.68-7.70 (d, J=8.7 Hz, 2H); 8.29 (s,1H); 8.35-8.38 (d, J=8.7 Hz, 2H); Anal. Calcd. for C₁₅H₁₄N₄O₂S: C,57.31; H, 4.49; N, 17.82. Found: C, 57.42; H, 4.51; N, 17.89.

EXAMPLE 5B 5-(4-aminophenyl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 5A for Example1D in Example 1E. m.p. 187-189° C.; MS(ESI(+)) m/e 285 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 1.18-1.21 (d, J=6.9 Hz, 6H); 3.02-3.11 (m, 1H);6.68-6.71 (d, J=8.4 Hz, 2H); 6.99-7.02 (d, J=8.4 Hz, 2H); 8.22 (s, 1H);Anal. Calcd. for C₁₅H₁₆N₄S.0.2C₄H₈O₂: C, 62.84; H, 5.87; N, 18.55.Found: C, 62.90; H, 5.47; N, 18.35.

EXAMPLE 5CN-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 5B and4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 418 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.22 (d, J=6.9 Hz, 6H); 2.25 (s, 3H); 3.00-3.09 (m, 1H);7.09-7.11 (d, J=8.1 Hz, 2H); 7.29-7.32 (d, J=8.7 Hz, 2H); 7.34-7.37 (d,J=8.7 Hz, 2H); 7.60-7.63 (d, J=8.7 Hz, 2H); 8.26 (s, 1H); 8.64 (s, 1H);8.85 (s, 1H); Anal. Calcd. for C₂₃H₂₃N₅OS.0.3H₂O: C, 65.32; H, 5.62; N,16.56. Found: C, 65.24; H, 5.68; N, 16.40.

EXAMPLE 6N-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 5B and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 169-171° C.; MS(ESI(+)) m/e 418(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.23 (d, J=6.9 Hz, 6H); 2.29(s, 3H); 3.00-3.09 (m, 1H); 6.79-6.82 (d, 1H, J=7.8 Hz); 7.14-7.19 (t,J=7.5 Hz, 1H); 7.24-7.27 (d, 1H, 8.1 Hz); 7.30-7.33 (m, 3H); 7.61-7.64(d, J=9 Hz, 2H); 8.26 (s, 1H); 8.67 (s, 1H); 8.88 (s, 1H); Anal. Calcd.for C₂₃H₂₃N₅OS: C, 66.16; H, 5.55; N, 16.77. Found: C, 65.95; H, 5.60;N, 16.53.

EXAMPLE 7N-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzenesulfonamide

The desired product was prepared by substituting Example 5B for Example1E in Example 2. MS(ESI(+)) m/e 425 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.14-1.16 (d, J=6.6 Hz, 6H); 2.84-2.93 (m, 1H); 7.19-7.22 (d, J=8.4 Hz,2H); 7.27-7.29 (d, J=8.4 Hz, 2H); 7.55-7.64 (m, 3H); 7.74-7.77 (d, 2H,J=6.6 Hz); 8.25 (s, 1H); 10.48 (s, 1H); Anal. Calcd. for C₂₁H₂₀N₄O₂S₂:C, 59.41; H, 4.75; N, 13.20. Found: C, 59.22; H, 4.48; N, 13.10.

EXAMPLE 8N-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzamide

The desired product was prepared by substituting Example 5B for Example1E in Example 4. m.p. >250° C.; MS(ESI) m/e 389 (M+H)⁺, 387 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 1.22-1.25 (d, J=6.6 Hz, 6H); 3.03-3.12 (m, 1H);7.41-7.43 (d, J=8.7 Hz, 2H); 7.53-7.65 (m, 3H); 7.93-7.02 (m, 4H); 8.46(s, 1H); 10.51 (s, 1H); HRMS (FAB) Calcd. for C₂₂H₂₀N₄OS: 389.1436.Found: 389.1451.

EXAMPLE 9N-[4-(4-amino-6-benzylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methylphenyl)ureaEXAMPLE 9A 6-benzyl-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting phenethylmagnesiumbromide for ethyl magnesium bromide in Examples 1A-1D. m.p. 231-233° C.;MS(ESI) m/e 363 (M+H)⁺, 361 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 4.00 (s,2H); 7.11-7.14 (d, 2H, J=6.9 Hz); 7.19-7.31 (m, 3H); 7.70-7.73 (d, J=9Hz, 2H); 8.29(s, 1H); 8.35-8.38 (d, J=9 Hz, 2H); Anal. Calcd. forC₁₉H₁₄N₄O₂S: C, 62.97; H, 3.89; N, 15.46. Found: C, 62.78; H, 3.99; N,15.47.

EXAMPLE 9B 5-(4-aminophenyl)-6-benzylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 9A for Example1D in Example 1E. m.p. 208-210° C.; MS(ESI) m/e 333 (M+H)⁺, 331 (M−H)⁻;¹H NMR (300 MHz, DMSO-d₆) δ 3.98 (s, 2H); 5.43 (s, 2H); 6.70-6.73 (d,J=8.4 Hz, 2H); 7.05-7.08 (d, J=8.4 Hz, 2H); 7.13-7.15 (d, 2H, 6.9 Hz);7.18-7.32 (m, 3H); 8.23 (s, 1H); Anal. Calcd. for C₁₉H₁₆N₄S.0.1CH₂Cl₂:C, 67.29; H, 4.79; N, 16.43. Found: C, 67.47; H, 4.78; N, 16.52.

EXAMPLE 9CN-[4-(4-amino-6-benzylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 9B and4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 169-173° C. MS(ESI) m/e 466 (M+H)⁺,464 (M−H)⁻, 500 (M+Cl)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 3H); 3.99(s, 2H); 7.08-7.37 (11H); 7.63-7.65 (d, 2H, J=8.7 Hz); 8.26 (s, 1H);8.64 (s, 1H); 8.86 (s, 1H); Anal. Calcd. for C₂₇H₂₃N₅OS: C, 69.66; H,4.98; N, 15.04. Found: C, 69.49; H, 4.94; N, 14.79.

EXAMPLE 10N-[4-(4-amino-6-benzylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 9B and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 466 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H); 3.99 (s, 2H); 6.79-6.82 (d, J=7.5 Hz, 1H);7.14-7.32 (m, 8H); 7.35-7.38 (d, J=8.7 Hz, 2H); 7.63-7.66 (d, J=8.4 Hz,2H); 8.26 (s, 1H); 8.67(s, 1H); 8.89 (s, 1H); Anal. Calcd. forC₂₇H₂₃N₅OS.0.75H₂O: C, 67.69; H, 5.15; N, 14.62. Found: C, 67.75; H,5.01; N, 14.60.

EXAMPLE 11N-[4-(4-amino-6-benzylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methylphenyl)urea

The desired product was prepared by substituting Example 9B and2-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 245-248° C.; MS(ESI) m/e 466 (M+H)⁺,464 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (s, 3H); 3.99 (s, 2H);6.94-6.99 (dt, J=1.2, 7.5 Hz, 1H); 7.14-7.32 (m, 7H); 7.35-7.38 (d,J=8.4 Hz, 2H); 7.65-7.68 (d, J=8.4 Hz, 2H); 7.80-7.83 (d, J=8.1 Hz, 1H);8.02 (s, 1H); 8.26 (s, 1H); 9.25 (s, 1H); Anal. Calcd. forC₂₇H₂₃N₅OS.0.1CH₂Cl₂: C, 68.66; H, 4.93; N, 14.77. Found: C, 68.53; H,4.74; N, 14.48.

EXAMPLE 12N-[4-(4-amino-6-isopropylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methylphenyl)urea

The desired product was prepared by substituting Example 5B and2-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 233-234° C.; MS(ESI(+)) m/e 418(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.21-1.23 (d, J=6.6 Hz, 6H); 2.26(s, 3H); 3.01-3.10 (m, 1H); 6.94-6.70 (dt, J=1.2 Hz, 7.5 Hz, 1H);7.13-7.21 (m, 2H); 7.30-7.33 (d, J=8.7 Hz, 2H); 7.63-7.66 (d, J=8.4 Hz,2H); 7.81-7.84 (d, J=8.1 Hz, 1H); 8.01(s, 1H); 8.26 (s, 1H); 9.24 (s,1H); Anal. Calcd. for C₂₃H₂₃N₅OS: C, 66.16; H, 5.55; N, 16.77. Found: C,66.20; H, 5.49; N, 16.82.

EXAMPLE 13N-[4-(4-amino-6-benzylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzenesulfonamide

The desired product was prepared by substituting Example 9B for Example1E in Example 2. m.p. 100-105° C.; MS(ESI) m/e 437 (M+H)⁺, 435 (M−H)⁻;¹H NMR (300 MHz, DMSO-d₆) δ 3.87 (s, 2H); 7.01-7.04 (d, 2H, J=8.1 Hz);7.16-7.33 (m, 7H); 7.53-7.65 (m, 3H); 7.75-7.78 (d, 2H, J=8.1 Hz); 8.25(s, 1H); 10.51 (s, 1H); Anal. Calcd. for C₂₅H₂₀N₄O₂S₂: C, 63.54; H,4.27; N, 11.86. Found: C, 63.27; H, 4.14; N, 11.82.

EXAMPLE 14N-{4-[4-amino-6-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)ureaEXAMPLE 14A (2E)-1-(4-nitrophenyl)-3-pyridin-4-ylprop-2-en-1-one

A suspension of 4′-nitroacetophenone (5 g, 30.3 mmol) and4-pyridinecarboxaldehyde (2.89 mL, 30.3 mmol) in water (45 mL) at roomtemperature was treated with 6% NaOH in H₂O/ethanol (2:1)(0.606 mL),stirred overnight, and filtered. The filter cake was washed with waterand small amount of ethanol then triturated with dichloromethane toprovide 1.95 g (25%) of the desired product. MS(ESI(+)) m/e 255 (M+H)⁺.

EXAMPLE 14B 1-(4-nitrophenyl)-3-pyridin-4-ylpropan-1-one

Trinbutyltin hydride (0.36 mL, 1.34 mmol) was added slowly by syringepump to a room temperature mixture of Example 14A (0.2 g, 0.78 mmol) andPd(PPh₃)₄ (27 mg, 0.023 mmol), stirred overnight, diluted with water,and extracted three times with ethyl acetate. The combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was putrified by flash column chromatography on silica gelwith 80% ethyl acetate/hexanes to provide 227 mg (100%) of the desiredproduct. MS(ESI(−)) m/e 255 (M−H)⁻.

EXAMPLE 14CN-{4-[4-amino-6-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 14B and3-methylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI) m/e 467 (M+H)⁺, 465 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 3.32 (s, 2H); 6.79-6.82 (d, J=7.5Hz, 1H); 7.13-7.30 (m, 5H); 7.32-7.35 (d, J=8.4 Hz, 2H); 7.61-7.64 (d,J=8.4 Hz, 2H); 8.28 (s, 1H); 8.45-8.47 (dd, J=4.2, 1.5 Hz, 2H); 8.67 (s,1H); 8.88 (s, 1H); HRMS (FAB) Calcd. for C₂₆H₂₃N₆OS: 467.1654. Found:467.1649.

EXAMPLE 15N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting 4-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 390(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s, 1H); 8.63 (s, 1H); 8.26 (s,1H); 7.62 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz,2H); 7.10 (d, J=8.4 Hz, 2H); 2.29 (s, 3H); 2.25 (s, 3H); Anal. Calcd.for C₂₁H₁₉N₅OS.0.5H₂O.0.1C₈H₁₈: C, 63.88; H, 5.36; N, 17.09. Found: C,63.98; H, 5.41; N, 16.90.

EXAMPLE 16N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting 3-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(−)) m/e 388(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 8.87 (s, 1H); 8.67 (s, 1H); 8.26 (s,1H); 7.63 (d, J=8.1 Hz, 2H); 7.32-7.23 (m, 4H); 7.17 (t, J=7.8 Hz, 1H);6.81 (d, J=7.8 Hz, 1H); 2.30 (s, 3H); 2.29 (s, 3H); Anal. Calcd. forC₂₁H₁₉N₅OS.0.5H₂O: C, 63.30; H, 5.06; N, 17.58. Found: C, 63.62; H,5.20; N, 17.38.

EXAMPLE 17N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methylphenyl)urea

The desired product was prepared by substituting 2-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 390(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H); 8.27 (s, 1H); 8.01 (s,1H); 7.82 (d, J=7.5 Hz, 1H); 7.64 (d, J=8.1 Hz, 2H); 7.31 (d, J=8.1 Hz,2H); 7.21-7.13 (m, 2H); 6.97 (t, J=7.5 Hz, 1H); 2.30 (s, 3H); 2.27 (s,3H); Anal. Calcd. for C₂₁H₁₉N₅OS.0.7H₂O: C, 62.73; H, 5.11; N, 17.42.Found: C, 62.91; H, 5.15; N, 17.10.

EXAMPLE 18N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting 3,5-dimethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 404(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.85 (s, 1H); 8.59 (s, 1H); 8.26 (s,1H); 7.62 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.09 (s, 2H); 6.63(s, 1H); 2.30 (s, 3H); 2.24 (s, 6H); Anal. Calcd. for C₂₂H₂₁N₅OS: C,65.49; H, 5.25; N, 17.36. Found: C, 65.19; H, 5.18; N, 17.24.

EXAMPLE 19N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared by substituting 3-methoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 406(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H); 8.76 (s, 1H); 8.26 (s,1H); 7.63 (d, J=8.7 Hz, 2H); 7.31 (d, J=8.7 Hz, 2H); 7.22-7.17 (m, 2H);6.95 (m, 1H); 6.57 (m, 1H); 3.74 (s, 3H); 2.30 (s, 1H); Anal. Calcd. forC₂₁H₁₉N₅O₂S.0.3H₂O: C, 61.39; H, 4.81; N, 17.04. Found: C, 61.41; H,4.65; N, 17.04.

EXAMPLE 20N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting 3-trifluoromethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 444(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H); 9.01 (s, 1H); 8.27 (s,1H); 8.03 (s, 1H); 7.67-7.59 (m, 3H); 7.53 (t, J=7.8 Hz, 1H); 7.33 (m,3H); 2.30 (s, 1H); Anal. Calcd. for C₂₁H₁₆F₃N₅OS: C, 56.88; H, 3.64; N,15.79. Found: C, 56.65; H, 3.51; N, 15.52.

EXAMPLE 21N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting 3-bromophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 454, 456(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H); 8.96 (s, 1H); 8.27 (s,1H); 7.88 (t, J=1.8 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 7.36-7.29 (m, 3H);7.25 (t, J=7.8 Hz, 1H); 7.19-7.14 (m, 1H); 2.30 (s, 3H); Anal. Calcd.for C₂₀H₁₆BrN₅OS: C, 52.87; H, 3.55; N, 15.41. Found: C, 52.56; H, 3.46;N, 15.21.

EXAMPLE 22N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-bromophenyl)urea

The desired product was prepared by substituting 4-bromophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 454, 456(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.93 (s, 1H); 8.90 (s, 1H); 8.26 (s,1H); 7.63 (d, J=8.7 Hz, 2H); 7.46 (s, 4H); 7.32 (d, J=8.7 Hz, 2H); 2.29(s, 3H); Anal. Calcd. for C₂₀H₁₆BrN₅OS.0.4H₂O-0.2C₈H₁₈: C, 53.56; H,4.24; N, 14.46. Found: C, 53.32; H, 3.96; N, 14.24.

EXAMPLE 23N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-fluorophenyl)urea

The desired product was prepared by substituting 2-fluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 394(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H); 8.63 (d, J=2.4 Hz,1H); 8.27 (s, 1H); 8.17 (td, J=8.1 Hz, 1.5 Hz, 1H); 7.64 (d, J=8.4 Hz,2H); 7.33 (d, J=8.4 Hz, 2H); 7.26 (ddd, J=12.0 Hz, 8.1 Hz, 1.2 Hz, 1H);7.16 (t, J=7.8 Hz, 1H); 7.05-6.99 (m, 1H); 2.30 (s, 3H); Anal. Calcd.for C₂₀H₁₆FN₅OS.0.2C₈H₁₈: C, 62.32; H, 4.10; N, 16.82. Found: C, 62.05;H, 4.68; N, 16.87.

EXAMPLE 24N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting 3-chlorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 410(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 2H); 8.27 (s, 1H); 7.73 (m,1H); 7.64 (d, J=8.7 Hz, 2H); 7.34-7.29 (m, 4H); 7.06-7.02 (m, 1H); 2.30(s, 1H); Anal. Calcd. for C₂₀H₁₆ClN₅OS.0.2H₂O: C, 58.09; H, 4.00; N,16.94. Found: C, 58.45; H, 3.99; N, 16.58.

EXAMPLE 25N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dimethoxyphenyl)urea

The desired product was prepared by substituting 3,5-dimethoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 436(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.85 (s, 1H); 8.75 (s, 1H); 8.26 (s,1H); 6.20 (d, J=8.4 Hz, 2H); 7.31(d, J=8.4 Hz, 2H); 6.70 (d, J=2.1 Hz,2H); 6.16 (t, J=2.1 Hz, 1H); 3.72 (s, 6H); 2.29 (s, 3H); Anal. Calcd.for C₂₂H₂₁N₅O₃S: C, 60.67; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.89;N, 15.92.

EXAMPLE 26N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting3-fluoro-5-trifluoromethylphenyl isocyanate for phenyl isocyanate inExample 1F. MS(ESI(+)) m/e 462 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.33(s, 1H); 9.13 (s, 1H); 8.27 (s, 1H); 7.73 (s, 1H); 7.67-7.62 (m, 3H);7.33 (d, J=8.7 Hz, 2H); 7.25 (d, J=8.4 Hz, 1H); 2.30 (s, 3H); Anal.Calcd. for C₂₁H₁₅F₄N₅OS: C, 54.66; H, 3.28; N, 15.18. Found: 54.47; H,3.06; N, 15.02.

EXAMPLE 27N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting4-fluoro-3-trifluoromethylphenyl isocyanate for phenyl isocyanate inExample 1F. MS(ESI(+)) m/e 462 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.12(s, 1H); 9.02 (s, 1H); 8.27 (s, 1H); 8.02 (dd, J=6.6 Hz, 2.7 Hz, 1H);7.70-7.62 (m, 3H); 7.45 (t, J=9.6 Hz); 7.32 (d, J=8.4 Hz, 2H); 2.30 (s,3H); Anal. Calcd. for C₂₁H₁₅F₄N₅OS.0.2H₂O: C, 54.24; H, 3.34; N, 15.06.Found: C, 54.13; H, 2.98; N, 14.85.

EXAMPLE 28N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-1,3-benzodioxol-5-ylurea

The desired product was prepared by substituting5-isocyanato-1,3-benzodioxole for phenyl isocyanate in Example 1F.MS(ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (s, 1H);8.63 (s, 1H); 8.26 (s, 1H); 7.61 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz,2H); 7.22 (d, J=1.8 Hz, 1H); 6.86-6.76 (m, 2H); 5.98 (s, 2H); 2.29 (s,3H); Anal. Calcd. for C₂₁H₁₇N₅O₃S: C, 60.13; H, 4.09; N, 16.70. Found:C, 57.91; H, 4.07; N, 15.65.

EXAMPLE 29N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methoxyphenyl)urea

The desired product was prepared by substituting 4-methoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 406(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (s, 1H); 8.56 (s, 1H); 8.27 (s,1H); 7.62 (d, J=8.1 Hz, 2H); 7.38 (d, J=9.0 Hz, 2H); 7.30 (d, J=8.1 Hz,2H); 6.89 (d, J=9.0 Hz, 2H); 3.73 (s, 3H); 2.30 (s, 3H).

EXAMPLE 30N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-chlorophenyl)urea

The desired product was prepared by substituting 4-chlorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 410(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (s, 1H); 8.89 (s, 1H); 8.26 (s,1H); 7.63 (d, J=8.7 Hz, 2H); 7.51 (s, J=9.0 Hz, 2H); 3.37-7.29 (m, 4H);2.29 (s, 3H).

EXAMPLE 31N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting2-fluoro-5-trifluoromethylphenyl isocyanate for phenyl isocyanate inExample 1F. MS(ESI(+)) m/e 462 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.39(s, 1H); 8.98 (d, J=2.7 Hz, 1H); 8.64 (dd, J=7.2 Hz, 1.8 Hz, 1H); 8.27(s, 1H); 7.65 (d, J=8.4 Hz, 2H); 7.52 (t, J=9.0 Hz, 1H); 7.44-7.37 (m,1H); 7.34 (d, J=8.4 Hz, 2H); 2.30 (s, 3H).

EXAMPLE 32 methyl3-[({[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl}amino]carbonyl)amino]benzoate

The desired product was prepared by substituting methyl3-isocyanatobenzoate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e434 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.04 (s, 1H); 8.94 (s, 1H); 8.27(s, 1H); 8.22 (t, 1H); 7.65 (d, 3H); 7.59 (dt, 1H); 7.44 (t, 1H); 7.32(d, 2H); 3.86 (s, 3H); 2.30 (s, 3H).

EXAMPLE 33N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-phenoxyphenyl)urea

The desired product was prepared by substituing 4-phenoxyphenylisocyanate for phenyl isocyanate. MS(ESI) m/e 468 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 8.88 (s, 1H); 8.77 (s, 1H); 8.26 (s, 1H); 7.64 (d, J=8.4Hz, 2H); 7.50 (d, J=8.4 Hz, 2H); 7.40-7.28 (m, 4H); 7.11(t, J=7.1 Hz,1H); 7.02-6.94 (m, 4H); 2.30 (s, 3H).

EXAMPLE 34N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(methylsulfanyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(methylsulfanyl)benzene for phenyl isocyanate in Example1F. MS(ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s, 1H);8.80 (s, 1H); 8.27 (s, 1H); 7.63 (d, J=8.4 Hz, 2H); 7.49 (t, J=1.5 Hz,1H); 7.31 (d, J=8.4 Hz, 2H); 7.23 (t, J=7.5 Hz, 1H); 7.17 (dt, J=9.0 Hz,1.5 Hz, 1H); 6.88 (dt, J=8.4 Hz, 1.5 Hz, 1H); 2.30 (s, 3H).

EXAMPLE 35N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,5-dimethylphenyl)urea

The desired product was prepared by substituting 2,5-dimethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 404(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (s, 1H); 8.27 (s, 1H); 7.94 (s,1H); 7.66 (s, 1H); 7.64 (d, J=9.0 Hz, 2H); 7.30 (d, J=9.0 Hz, 2H); 7.06(d, J=7.2 Hz, 1H); 7.87 (d, J=7.4 Hz, 1H); 2.30 (s, 3H); 2.26 (s, 3H);2.21 (s, 3H).

EXAMPLE 36N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-chlorophenyl)urea

The desired product was prepared by substituting 2-chlorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 410, 412(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.64 (s, 1H); 8.40 (s, 1H); 8.27 (s,1H); 8.17 (dd, J=8.4 Hz, 1.8 Hz, 1H); 7.65 (d, J=8.4 Hz, 2H); 7.48 (dd,J=7.8 Hz, 1.8 Hz, 1H); 7.36-7.28 (m, 3H); 7.05 (td, J=8.4 Hz, 1.8 Hz,1H); 2.30 (s, 1H).

EXAMPLE 37N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dichlorophenyl)urea

The desired product was prepared by substituting 3,5-dichlorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 444, 446(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H); 9.11 (s, 1H); 8.27 (s,1H); 7.64 (d, J=8.4 Hz, 2H); 7.56 (d, J=1.8 Hz, 2H); 7.33 (d, J=8.4 Hz,2H); 7.19 (t, J=1.8 Hz, 1H); 2.29(s, 3H).

EXAMPLE 38N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chloro-4-methylphenyl)urea

The desired product was prepared by substituting 3-chloro-4-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 424(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.93 (s, 1H); 8.85 (s, 1H); 8.27 (s,1H); 7.71 (d, J=1.8 Hz, 1H); 7.63 (d, J=8.4 Hz, 2H); 7.31 (d, J=8.4 Hz,2H); 7.26 (d, J=8.4 Hz, 1H); 7.21 (dd, J=8.4 Hz, 1.8 Hz, 1H); 2.29 (s,3H); 2.27 (s, 3H).

EXAMPLE 39N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,6-difluorophenyl)urea

The desired product was prepared by substituting 2,6-difluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 412(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H); 8.26 (s, 1H); 8.20 (s,1H); 7.63 (d, 1H); 7.36-7.27 (m, 3H); 7.22-7.10 (m, 2H); 2.29 (s, 1H).

EXAMPLE 40N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting2-chloro-5-trifluoromethylphenyl isocyanate for phenyl isocyanate inExample 1F. MS(ESI) m/e 478 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (s,1H); 8.70 (s, 1H); 8.65 (d, J=2.1 Hz, 1H); 8.27 (s, 1H); 7.74 (d, J=8.4Hz, 1H); 7.66 (d, J=8.7 Hz, 2H); 4.41 (dd, J=8.4 Hz, 2.1 Hz, 1H); 7.35(d, J=8.7 Hz, 2H); 2.30 (s, 3H).

EXAMPLE 41N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting 3-ethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 404(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.86 (s, 1H); 8.68 (s, 1H); 8.27 (s,1H); 7.63 (d, J=8.7 Hz, 2H); 7.31 (d, J=8.7 Hz, 2H); 7.35-7.25 (m, 2H);7.20 (t, J=7.8 Hz, 1H); 6.84(d, J=7.2 Hz, 1H); 2.58 (q, J=7.5 Hz, 2H);2.30 (s, 3H); 1.19 (t, J=7.5 Hz, 3H).

EXAMPLE 42N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-ethylphenyl)urea

The desired product was prepared by substituting 4-ethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 404(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.85 (s, 1H); 8.65 (s, 1H); 8.27 (s,1H); 7.63 (d, J=8.4 Hz, 2H); 9.38 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz,2H); 7.13 (d, J=8.4 Hz, 2H); 2.51 (q, J=7.8 Hz, 2H); 2.29 (s, 3H); 1.16(t, J=7.8 Hz, 3H).

EXAMPLE 43N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-bromo-2-fluorophenyl)urea

The desired product was prepared by substituting 2-fluoro-4-bromophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 474(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H); 8.73 (d, J=2.4 Hz,1H); 8.27 (s, 1H); 8.15 (t, J=8.7 Hz, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.59(dd, J=10.8 Hz, 2.1 Hz, 1H); 7.38 (m, 1H); 7.33 (d, J=8.7 Hz, 2H); 2.29(s, 1H).

EXAMPLE 44N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting 2-fluoro-5-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI) m/e 408 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H); 8.56 (d, J=2.7 Hz, 1H); 8.27(s, 1H); 8.00 (dd, J=8.1 Hz, 2.1 Hz, 1H); 7.63 (d, J=9.0 Hz, 2H); 7.32(d, J=9.0 Hz, 2H); 7.12 (dd, J=11.4 Hz, 8.1 Hz, 1H); 6.82 (m, 1H); 2.30(s, 3H); 2.28 (s, 3H).

EXAMPLE 45N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-Ny-[4-chloro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting4-chloro-3-trifluoromethylphenyl isocyanate for phenyl isocyanate inExample 1F. MS(ESI(+)) m/e 478 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.25(s, 1H); 9.07 (s, 1H); 8.27 (s, 1H); 8.13 (d, J=2.4 Hz, 1H); 7.70-7.60(m, 4H); 7.33 (d, J=8.4 Hz, 2H); 2.30 (s, 3H).

EXAMPLE 46N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,4-dimethylphenyl)urea

The desired product was prepared by substituting 3,4-dimethylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 404(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s, 1H); 8.56 (s, 1H); 8.26 (s,1H); 7.62 (d, J=8.4 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.25 (s, 1H); 7.19(d, J=8.1 Hz, 1H); 7.04 (d, J=8.1 Hz, 1H); 2.30 (s, 3H); 2.20 (s, 3H);2.16 (s, 3H).

EXAMPLE 47N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-chloro-5-methylphenyl)urea

The desired product was prepared by substituting 2-chloro-5-methylphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 424(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.61 (s, 1H); 8.32 (s, 1H); 8.27 (s,1H); 8.02 (d, J=2.1 Hz, 1H); 7.65 (d, J=8.7 Hz, 2H); 7.36-7.31 (m, 3H);6.87 (dd, J=8.7 Hz, 2.1 Hz, 1H); 2.30 (s, 6H).

EXAMPLE 48N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methoxyphenyl)urea

The desired product was prepared by substituting 2-methoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 406(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H); 8.31 (s, 1H); 8.27 (s,1H); 8.15 (dd, J=7.8 Hz, 2.1 Hz, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.31 (d,J=8.7 Hz, 2H); 7.04 (dd, J=8.1 Hz, 1.8 Hz, 1H); 6.70-6.87 (m, 2H); 3.90(s, 3H); 2.30 (s, 3H).

EXAMPLE 49N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,5-dichlorophenyl)urea

The desired product was prepared by substituting 2,5-dichlorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 444(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H); 8.55 (s, 1H); 8.33 (d,J=2.4 Hz, 1H); 8.27 (s, 1H); 7.65 (d, J=8.7 Hz, 2H); 7.52 (d, J=8.4 Hz,1H); 7.34 (d, J=8.7 Hz, 2H); 7.12 (dd, J=8.4 Hz, 2.4 Hz, 1H); 2.20 (s,3H).

EXAMPLE 50N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,4-difluorophenyl)urea

The desired product was prepared by substituting 2,4-difluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 412(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H); 8.59 (s, 1H); 8.27 (s,1H); 8.09 (td, J=9.6 Hz, 6.0 Hz, 1H); 7.63 (d, J=8.4 Hz, 2H); 7.37-7.28(m, 3H); 7.07 (m, 1H); 2.29 (s, 3H).

EXAMPLE 51N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,4,5-trimethoxyphenyl)urea

The desired product was prepared by substituting 3,4,5-trimethoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 466(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H); 8.70 (s, 1H); 8.27 (s,1H); 7.63 (d, J=8.4 Hz, 2H); 7.31 (d, J=8.4 Hz, 2H); 6.83 (s, 2H); 3.76(s, 6H); 3.62 (s, 3H); 2.30 (s, 3H).

EXAMPLE 52N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,5-dimethoxyphenyl)urea

The desired product was prepared by substituting 2,5-dimethoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 436(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H); 8.33 (s, 1H); 8.27 (s,1H); 7.88 (d, J=3.0 Hz, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.31 (d, J=8.7 Hz,2H); 6.94 (d, J=9.0 Hz, 1H); 6.51 (dd, J=9.0 Hz, 3.0 Hz, 1H); 3.84 (s,3H); 3.70 (s, 3H); 2.30 (s, 3H).

EXAMPLE 53N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-2-naphthylurea

The desired product was prepared by substituting 2-naphthyl isocyanatefor phenyl isocyanate in Example 1F. MS(ESI) m/e 426 (M+H); ¹H NMR (300MHz, DMSO-d₆) δ 8.99 (s, 1H); 8.98 (s, 1H); 8.27 (s, 1H); 8.13 (d, J=2.1Hz, 1H); 7.83 (m, 3H); 7.68 (d, J=8.4 Hz, 2H); 7.52 (dd, J=8.7 Hz, 2.1Hz, 1H); 7.46 (t, J=7.5 Hz, 1H); 7.40-7.31 (m, 3H).

EXAMPLE 54N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-benzylurea

The desired product was prepared by substituting benzyl isocyanate forphenyl isocyanate in Example 1F. MS(ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 8.81(s, 1H); 8.26 (s, 1H); 7.59 (d, J=8.7 Hz, 2H);8.38-7.28 (m, 4H); 7.27-7.22 (m, 3H); 6.71(t, J=6.0 Hz, 1H); 4.33 (d,J=6.0 Hz, 2H); 2.28 (s, 3H).

EXAMPLE 55N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-cyanophenyl)urea

The desired product was prepared by substituting 4-cyanophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 401(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H); 9.08 (s, 1H); 8.27 (s,1H); 7.75 (d, J=9.0 Hz, 2H); 7.69-7.62 (m, 4H); 7.34 (d, J=8.4 Hz, 2H);2.29 (s, 3H).

EXAMPLE 56N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(dimethylamino)phenyl]urea

The desired product was prepared by substituting 4-dimethylaminophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 419(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (s, 1H); 8.37 (s, 1H); 8.26 (s,1H); 7.61 (d, J=8.4 Hz, 2H); 7.28 (m, 4H); 6.71 (d, J=9.0 Hz, 2H); 2.84(s, 6H); 2.29 (s, 3H).

EXAMPLE 57N-(4-{4-amino-6-[(4-methylpiperazin-1-yl)methyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)ureaEXAMPLE 57A6-(bromomethyl)-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 1D (500 mg, 1.75 mmol) in benzene (50 mL) wastreated with NBS (340 mg, 1.91 mmol) and AIBN (50 mg), stirred at refluxfor 3.5 hours, and concentrated. The concentrate was absorbed ontosilica gel and purified by flash column chromatography with ethylacetate to provide 330 mg of a 1.7:1 mixture of the desired product andrecovered starting material.

EXAMPLE 57B6-[(4-methylpiperazin-1-yl)methyl]-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A mixture of Example 57A (330 mg) and N-methylpiperazine (0.3 mL, 2.71mmol) in DMF (6 mL) was stirred at room temperature overnight andconcentrated. The concentrate was absorbed on silica gel and purified byflash column chromatography with ethyl acetate fillowed by 12%methanol/dichloromethane to provide 115 mg the desired product.R_(f)=0.38 (12% methanol/dichloromethane).

EXAMPLE 57C5-(4-aminophenyl)-6-[(4-methylpiperazin-1-yl)methyl]thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 57B for Example1D in Example 1E. MS(ESI(+)) m/e 355 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.24 (s, 1H); 6.98 (d, J=8.4 Hz, 2H); 6.68 (d, J=8.4 Hz, 2H); 5.41 (brs, 2H); 3.50 (s, 2H); 2.48 (s, 3H); 2.45 (br s), 4H); 2.26 (br s, 4H).

EXAMPLE 57DN-(4-{4-amino-6-[(4-methylpiperazin-1-yl)methyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 57C and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H);8.68 (s, 1H); 8.27 (s, 1H); 7.62 (d, J=9.0 Hz, 2H); 7.32-7.23 (m, 4H);7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=7.5 Hz, 1H); 3.50 (s, 2H); 2.45-2.20(br s), 8H); 2.29 (s, 3H); 2.14 (s, 3H).

EXAMPLE 58N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 58A 2-[1-(4-nitrophenyl)ethylidene]malononitrile

A mixture of 1-(4-nitrophenyl)ethanone (15 g, 90.8 mmol), malononitrile(6 g, 90.8 mmol), ammonium acetate (7 g, 90.8 mmol) and acetic acid (10mL) in benzene (200 mL) was stirred at reflux overnight in a flaskequipped with a Dean-Stark trap. The reaction mixture was cooled to roomtemperature, poured into water, and extracted three times with ethylacetate. The combined organic extracts were washed with water and brine,dried (MgSO₄), filtered, and concentrated. The residue was purified bysilica gel chromatography eluting with 25% ethyl acetate/hexanes toprovide 9.42 g of the desired product. R_(f)=0.33 (25% ethylacetate/hexanes).

EXAMPLE 58B 2-amino-4-(4-nitrophenyl)thiophene-3-carbonitrile

A solution of Example 58A (4.14 g, 19.6 mmol) in ethanol (200 mL) andTHF (80 mL) at room temperature was treated sequentially with sulfur(621 mg, 19.4 mmol) and triethylamine (1.82 mL, 19.4 mmol), stirredovernight, and filtered. The filter cake was absorbed on silica andpurified by flash column chromatography with 3:2 hexanes/ethyl acetateto provide 2.51 g of the desired product.

EXAMPLE 58C 5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 58B (1.23 g, 5.01 mmol) in formamide (20 mL) washeated to between 150 and 160° C. for 19 hours, cooled to roomtemperature, and filtered. The filter cake was dried to give 1.09 g ofthe desired product. MS (ESI(+)) m/e 273 (M+H)⁺.

EXAMPLE 58D 5-(4-aminophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 58C (0.5 g, 1.83 mmol) in THF (30 mL), water (15mL), and ethanol (40 mL) was heated to 50° C., treated with iron powder(0.616 g, 11.02 mmol), heated to between 70 and 80° C. for two hours,and filtered while hot through diatomaceous earth (Celite®). The pad waswashed with THF (10 mL) and ethanol and the combined filtrates wereconcentrated. The residue was partitioned between water and ethylacetate and the aqueous phase was extracted three times with ethylacetate. The combined extracts were washed with brine, dried (MgSO₄),filtered, and concentrated to give 0.432 g of the desired product. MS(CI) m/e 243 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (s, 1H); 7.28 (s,1H); 7.11 (d, J=8.4 Hz, 2H); 6.68 (d, J=8.4 Hz, 2H); 5.39 (br s, 2H).

EXAMPLE 58EN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 58D and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 376 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.88 (s, 1H); 8.67 (s, 1H); 8.34 (s, 1H); 7.61 (d, J=8.7 Hz,2H); 7.43(s, 1H); 7.39 (d, J=8.7 Hz, 2H); 7.31 (s, 1H); 7.25 (d, J=7.5Hz, 1H); 7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=7.5 Hz, 1H); Anal. Calcd.for C₂₀H₁₇N₅OS: C, 63.98; H, 4.56; N, 18.65. Found: C, 63.65; H, 4.56;N, 18.36.

EXAMPLE 59N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 58D for Example1E in Example 1F. MS(ESI(+)) m/e 362 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (s, 1H); 8.75 (s, 1H); 8.34 (s, 1H); 7.61 (d, J=8.4 Hz, 2H); 7.47(d, J=7.5 Hz, 2H); 7.43 (s, 1H); 7.40 (d, J=8.4 Hz, 2H); 7.30 (t. J=7.5Hz, 1H); 6.98 (t, J=7.5 Hz, 1H); Anal. Calcd. for C₁₉H₁₅N₅OS.0.2H₂O: C,62.52; H, 4.25; N, 19.19. Found: C, 52.65; H, 4.13; N, 18.86.

EXAMPLE 60N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product prepared by substituting Example 58D and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.86 (s, 1H); 8.68 (s, 1H); 8.33 (s, 1H); 7.61 (d, 2H); 7.43(s, 1H); 7.39 (d, 2H); 7.34 (s, 1H); 7.27 (d, 1H); 7.19 (s, 1H); 6.83(s, 1H); 2.58 (q, 2H); 1.18 (t, 3H); Anal. Calcd. for C₂₁H₁₉N₅OS: C,64.76; H, 4.92; N, 17.98. Found: C, 64.38; H, 4.93; N, 17.68.

EXAMPLE 61N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 61A 6-bromo-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 58C (50 mg, 0.18 mmol) in acetic acid (1 mL) andDMF (3 mL) was heated with a heat gun to obtain a clear solution, cooledto 0° C., and treated with bromine (0.02 mL). The reaction mixture wasstirred at 0° C. for 1 hour, diluted with saturated NaHCO₃, andfiltered. The filter cake was dried to provide 56 mg of the desiredproduct.

EXAMPLE 61B 5-(4-aminophenyl)-6-bromothieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 61A for Example1D in Example 1E. MS(ESI(+)) m/e 321, 323 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.29 (s, 1H); 7.05 (d, J=8.4 Hz, 2H); 6.70 (d, J=8.4 Hz, 2H);5.50 (s, 2H).

EXAMPLE 61CN-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by Example 61B for and 3-methylphenylisocyanate for Example 1E and phenyl isocyanate, respectively, inExample 1F. MS(ESI(+)) m/e 454, 456 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.92 (s, 1H); 8.69 (s, 1H); 8.33 (s, 1H); 7.65 (d, J=8.4 Hz, 2H);7.36(d, J=8.4 Hz, 2H); 7.32 (s, 1H); 7.26 (d, J=7.8 Hz, 1H); 7.17 (t,J=7.8 Hz, 1H); 6.81 (d, J=7.8 Hz, 1H); Anal. Calcd. forC₂₀H₁₆BrN₅OS.0.4H₂O: C, 52.05; H, 3.67; N, 15.17. Found: C, 52.07; H,3.36; N, 15.13.

EXAMPLE 624-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-N-(3-chlorophenyl)benzamide

The desired product was prepared by substituting 3-chloroaniline foraniline in Example 66. MS(ESI(−)) m/e 393 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ 10.57 (s, 1H); 8.30 (s, 1H); 8.12 (d, J=8.4 Hz, 2H); 8.01 (t,J=1.8 Hz, 1H); 7.73 (m, 1H); 7.60 (d, J=8.4 Hz, 2H); 7.41 (t, J=7.2 Hz,1H); 7.19 (m, 1H); 2.32 (s, 3H).

EXAMPLE 63 5-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting2-amino-4,6-dimethylphenol for 2-aminophenol in Example 3. MS(ESI(+))m/e 402 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H); 8.27 (s, 1H);7.93 (d, J=8.4 Hz, 2H); 7.41 (d, J=8.4 Hz, 2H); 7.11 (s, 1H); 6.80 (s,1H); 2.41 (s, 3H); 2.34 (s, 3H); 2.31 (s, 3H); Anal. Calcd. forC₂₂H₁₉N₅OS.0.2H₂O: C, 65.78; H, 5.08; N, 16.82. Found: C, 65.41; H,4.90; N, 17.15.

EXAMPLE 64N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-2-(3-methylphenyl)acetamide

The desired product was prepared by substituting 3-methylphenylacetylchloride for benzoyl chloride in Example 4. MS(ESI(+)) 389 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H); 8.26 (s, 1H); 7.78 (d, J=8.4 Hz,2H); 7.32 (d, J=8.4 Hz, 2H); 7.26-7.13 (m, 3H); 7.07 (d, J=7.5 Hz, 1H);3.64 (s, 2H); 2.31 (s, 3H); 2.27 (s, 3H); Anal. Calcd. for C₂₂H₂₀N₄OS:C, 68.02; H, 5.19; N, 14.42. Found: C, 67.76; H, 5.29; N, 14.31.

EXAMPLE 65N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-3-methylbenzamide

The desired product was prepared by substituting 3-methylbenzoylchloride for benzoyl chloride in Example 4. MS (CI) m/e 375 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 10.42 (s, 1H); 8.28 (s, 1H); 7.98 (d, J=8.4 Hz,2H); 7.80-7.75 (m, 2H); 7.45-7.36 (m, 4H); 2.42 (s, 3H); 2.31 (s, 3H);Anal. Calcd. for C₁₂H₁₈N₄OS.0.2C₄H₈O₂: C, 66.78; H, 5.04; N, 14.29.Found: H, 66.55; H, 6.29; N, 13.95.

EXAMPLE 664-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-N-phenylbenzamideEXAMPLE 66A 5-(4-bromophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 4-bromophenylethylketone for Example 1A in Examples 1B and 1C. MS(ESI(+)) 320, 322 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 8.278 (s, 1H); 7.74 (d, J=8.1 Hz, 2H); 7.36(d, J=8.1 Hz, 2H); 2.28 (s, 3H).

EXAMPLE 66B 4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)benzoic acid

A −78° C. solution of Example 66A (1.5 g, 4.68 mmol) in THF (50 mL) wastreated dropwise with 2.5M n-butyllithium in hexanes (4.7 mL, 11.71mmol), stirred for 30 minutes at −78° C., then treated with excess dryice. The reaction was stirred at −78° C. for 30 minutes, warmed to roomtemperature, diluted with water, adjusted to pH 3 with 2N HCl, andfiltered. The filter cake was dried to provide 686 mg (51%) of thedesired product. MS (CI) m/e 285 (M⁺); ¹H NMR (300 MHz, DMSO-d₆) δ 13.13(br s, 1H); 8.29 (s, 1H); 8.09 (d, J=8.4 Hz, 2H); 7.53 (d, J=8.4 Hz,2H); 2.28 (s, 3H).

EXAMPLE 66C4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-N-phenylbenzamide

A suspension of Example 66B (89 mg, 0.31 mmol) and HOBT (46 mg, 0.35mmol) in DMF (4 mL) at room temperature was treated with aniline (0.029mL, 0.31 mmol), NMM (0.086 mL, 0.78 mmol) and EDC.HCl (66 mg, 0.34mmol), stirred overnight, and partitioned between water and ethylacetate. The aqueous phase was extracted three times with ethyl acetateand the combined organic extracts ware washed with water, and brine,dried (Na₂SO₄), filtered, and concentrated to a volume of about 3 mL.The product was treated with hexanes and the resulting precipitate wascollected by filtration to provide 84 mg (75%) of the desired product.MS(ESI(+)) m/e 361 (M+H); ¹H NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H);8.30 (s, 1H); 8.12 (d, J=8.4 Hz, 2H); 7.80 (d, J=7.5 Hz, 2H); 7.58 (d,J=8.4 Hz, 2H); 7.37 (t, J=7.5 Hz, 2H); 7.12 (t, J=7.5 Hz, 1H); 2.32 (s,3H); Anal. Calcd. for C₂₀H₁₆N₄OS.0.1C₄H₈O₂: C, 66.36; H, 4.59; N, 15.17.Found: 66.07; H, 4.76; N, 15.32.

EXAMPLE 674-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-N-(3-methylphenyl)benzamide

The desired product was prepared by substituting 3-methylaniline foraniline in Example 66C. MS(ESI(+)) 375 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 10.33 (s, 1H); 8.30 (s, 1H); 8.11 (d, J=8.1 Hz, 2H); 7.66 (s, 1H);7.61-7.55 (m, 3H); 7.25 (t, J=7.5 Hz, 1H); 6.94 (d, J=7.5 Hz, 1H); 2.32(s, 6H).

EXAMPLE 68N-(4-{4-amino-6-[(dimethylamino)methyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting dimethylamine forN-methylpiperazine in Examples 57B-D. MS(ESI(+)) m/e 433 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 8.92 (s, 1H); 8.71 (s, 1H); 8.28 (s, 1H); 7.32-7.22(m, 4H); 7.17 (t, J=7.8 Hz, 1H); 6.81 (d, J=7.8 Hz, 1H); 3.45 (br s,2H); 2.29 (s, 3H); 2.17 (s, 6H).

EXAMPLE 69N-{4-[4-amino-6-(morpholin-4-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting morpholine forN-methylpiperazine in Examples 57B-D. MS(ESI(+)) m/e 475 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 8.90 (s, 1H); 8.69 (s, 1H); 8.28 (s, 1H); 7.63 (d,J=8.7 Hz, 2H); 7.33-7.23 (m, 4H); 7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=7.5Hz, 1H); 3.56 (br s, 4H); 3.51 (s, 2H); 2.36 (br s, 4H); 2.29 (s, 3H);Anal. Calcd. for C₂₅H₂₆N₆O₂S.0.5H₂O: C, 62.09; H, 5.63; N, 17.38. Found:C, 62.20; H, 5.46; N, 17.41.

EXAMPLE 70N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzenesulfonamideEXAMPLE 70A5-(4-amino-3-methoxyphenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting3-methoxy-4-nitrobenzoyl chloride for 4-nitrobenzoyl chloride inExamples 1A-1E.

EXAMPLE 70BN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzenesulfonamide

The desired product was prepared by substituting Example 70A for Example1E in Example 2. MS(ESI(+)) m/e 427 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.64 (s,1H); 8.26 (s, 1H); 7.70-7.67 (m, 2H); 7.65-7.53 (m, 3H); 7.37 (d, 1H,J=7.8 Hz); 6.93-6.90 (m, 2H); 3.44 (s, 3H); 2.26 (s, 3H).

EXAMPLE 715-[4-(1,3-benzoxazol-2-ylamino)-3-methoxyphenyl]-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 70A for Example1E in Example 3. MS(ESI (+)) m/e 404 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.86 (s,1H); 8.44 (d, 1H, J=8.1 Hz); 8.28 (s, 1H); 7.51-7.46 (m, 2H); 7.26-7.21(m, 1H); 7.17-7.10 (m, 2H); 7.05 (dd, 1H, J=1.7, 8.1 Hz); 3.90 (s, 3H);2.35 (s, 3H).

EXAMPLE 72N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 70A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 440 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 9.60 (s, 1H); 8.45 (s, 1H); 8.29 (d, J=8.1 Hz, 1H); 8.27 (s, 1H); 7.76(t, J=2.0 Hz, 1H); 7.32 (t, J=8.1 Hz, 1H); 7.26-7.22 (m, 1H); 7.06-7.01(m, 2H); 6.93 (dd, J=1.7, 8.1 Hz, 1H); 3.92 (s, 3H); 2.33 (s, 3H).

EXAMPLE 73N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 70A and4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 9.29 (s, 1H); 8.37 (s, 1H); 8.31 (d, 1H, J=8.1 Hz); 8.26 (s, 1H); 7.35(d, 2H, J=8.5 Hz); 7.10 (d, 2H, J=8.1 Hz); 7.03 (d, 1H, J=2.0 Hz);6.93-6.89 (m, 1H); 3.91 (s, 3H); 2.32 (s, 3H); 2.25 (s, 3H).

EXAMPLE 74N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 70A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 9.32 (s, 1H); 8.40 (s, 1H); 8.32 (d, 1H, J=8.1 Hz); 8.27 (s, 1H);7.33-7.31 (br s, 1H); 7.27-7.24 (m, 1H); 7.17 (t, 1H, J=7.5 Hz); 7.04(d, 1H, J=1.7 Hz); 6.92 (dd, 1H, J=1.7, 8.2 Hz); 6.80 (d, 1H, J=7.5 Hz);3.91 (s, 3H); 2.33 (s, 3H); 2.29 (s, 3H).

EXAMPLE 75N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 70A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 434 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 9.25 (s, 1H); 8.38 (s, 1H); 8.31 (d, 2H, J=8.1 Hz); 8.27 (s, 1H); 7.10(s, 2H); 7.03 (d, 1H, J=1.7 Hz); 6.91 (dd, 2H, J=1.7, 8.1 Hz); 6.63 (s,1H); 3.91 (s, 3H); 2.33 (s, 3H); 2.24 (s, 6H).

EXAMPLE 76N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,3-dichlorobenzenesulfonamide

The desired product was prepared by substituting Example 70A for and2,3-dichlorobenzenesulfonyl chloride for Example 1E and benzenesulfonylchloride, respectively, in Example 2. MS(ESI(+)) m/e 495 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 10.03 (s, 1H); 8.26 (s. 1H); 7.91 (d, 1H, J=7.8 Hz);7.80-7.77 (m, 1H); 7.48 (t, 1H, J=7.8 Hz); 7.33 (d, 1H, J=8.8 Hz);6.93-6.90 (m, 2H); 3.46 (s, 3H); 2.26 (s, 3H).

EXAMPLE 77N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]quinolin-2-amine

A mixture of Example 70A (100 mg, 0.35 mmol) and 2-chloroquinoline (62mg, 0.38 mmol) was heated to 200° C. under nitrogen for 20 minutes,cooled to room temperature, and partitioned between saturated NaHCO₃ anddichloromethane. The aqueous phase was extracted three times withdichloromethane and the combined organic extracts were dried (Na₂SO₄),filtered, and concentrated. The concentrate was triturated with diethylether to provide 6 mg (5%) of the desired product. MS(ESI(+)) m/e 414(M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.08 (d, 1H, J=8.2 Hz); 8.70 (s, 1H); 8.28(s, 1H); 8.08 (d, 1H, J=8.8 Hz); 7.73 (t, 2H, J=8.8 Hz); 7.61-7.56 (m,1H); 7.44 (d, 1H, J=9.1 Hz); 7.34-7.29 (m, 1H); 7.06 (d, 1H, J=2.0 Hz);7.02-6.99 (m, 1H); 3.93 (s, 3H); 2.37 (s, 3H).

EXAMPLE 78N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 78A 5-(4-aminophenyl)-6-ethylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by subsituting n-propylmagnesiumchloride for ethylmagnesium chloride in Examples 1A-1E. ¹H NMR (DMSO-d₆)δ 8.22 (s, 1H); 7.00 (d, J=8.4 Hz, 2H); 6.68 (d, J=8.4 Hz, 2H); 5.39 (s,2H); 2.63 (q, J=7.5 Hz, 2H); 1.17 (t, J=7.5 Hz, 3H).

EXAMPLE 78BN-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared substituting Example 78A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 404.10 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 8.84 (s,1H); 8.64 (s,1H); 8.24 (s, 1H); 7.62 (d, J=8.5 Hz,2H); 7.10-7.35 (m, 5H); 6.80 (d, J=7.2 Hz, 1H); 2.62 (q, J=7.5 Hz, 2H);2.24 (s,3H); 1.18 (t, J=7.5 Hz, 3H).

EXAMPLE 79N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 78A and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.24 (s, 1H); 8.59 (d,J=2 Hz, 1H); 8.24 (s, 1H); 8.00 (dd, J=8.1, 2.4 Hz, 1H); 7.63 (d, J=8.4Hz, 2H); 7.32 (d, J=8.4 Hz, 2H); 7.12 (dd, J=12.0, 8.5 Hz, 2H); 6.92(m,1H); 3.24 (s,3H); 2.64 (q, J=7.5 Hz, 2H); 1.19 (t, J=7.5 Hz, 3H).

EXAMPLE 80N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-methoxyphenyl)urea

The desired product was prepared by substituting Example 78A and4-methoxyphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 8.81 (s, 1H); 8.58 (s,1H); 8.23 (s,1H); 7.61 (d, J=8.7 Hz, 2H); 7.38 (d, J=9.2 Hz, 2H);7.29(d, J=8.7 Hz, 2H); 6.88 (d, J=9.2 Hz, 2H); 3.66 (s,3H); 2.63 (q,J=7.5 Hz, 2H); 1.18 (t, J=7.5 Hz, 3H).

EXAMPLE 81N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N-(4-chlorophenyl)urea

The desired product was prepared by substituting Example 78A and4-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 8.93 (s,1H); 8.90(s,1H); 7.62 (d, J=8.7 Hz, 2H); 7.51 (d, J=9.0 Hz, 2H); 7.20-7.40 (m,4H); 2.63 (q, J=7.5 Hz, 2H); 1.16 (t, J=7.5 Hz, 3H).

EXAMPLE 82N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 78A and3-trifluoromethyl-4-fluorophenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.16 (s,1H);9.07 (s,1H); 8.31 (s, 1H); 8.28 (dd, J=6.3, 2.5 Hz, 1H); 7.64 (d, J=8.4Hz, 3H); 7.45 (t, J=9.9 Hz, 1H); 7.33 (d, J=8.4 Hz, 2H); 2.64 (q, J=7.5Hz, 2H); 1.18 (t, J=7.5 Hz, 3H).

EXAMPLE 83N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,5-difluorophenyl)urea

The desired product was prepared by substituting Example 78A and2,5-difluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H); 8.83 (s,1H); 8.32 (s, 1H); 8.0-8.10 (m, 1H); 7.62 (d, J=8.4 Hz, 2H); 7.35 (d,J=8.4 Hz, 2H); 7.26 (m, 1H); 6.8-6.90 (m, 1H); 2.63 (q, J=7.5 Hz, 2H);1.18 (t, J=7.5 Hz, 3H).

EXAMPLE 84N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-fluorophenyl)urea

The desired product was prepared by substituting Example 78A and2-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.30 (s, 1H); 8.62 (d,J=2.7 Hz, 1H); 8.32 (s, 1H); 8.17 (dt, J=8.7, 1.5 Hz, 1H); 7.63 (d,J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.0-7.32 (m, 3H); 2.66 (q, J=7.5Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 85N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,4-difluorophenyl)urea

The desired product was prepared by substituting Example 78A and2,4-difluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.25 (s, 1H); 8.60 (d,J=2.0 Hz, 1H); 8.32 (s, 1H); 8.00-8.15 (m, 1H); 7.62 (d, J=8.4 Hz, 2H);7.25-8.00 (m,3H); 7.00-7.16 (m, 1H); 2.63 (q, J=7.5 Hz, 2H); 1.98 (t,J=7.5 Hz, 3H).

EXAMPLE 86N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2,6-difluorophenyl)urea

The desired product was prepared by substituting Example 78A and2,6-difluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.22 (s, 1H); 8.32 (s,1H); 8.22 (s, 1H); 7.63 (d, J=8.4 Hz, 2H); 7.22-7.40 (m, 3H); 7.10-7.20(m, 2H); 2.62 (q, J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 87N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared by substituting Example 78A and3-methoxyphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 8.95 (s, 1H); 8.80 (s,1H); 8.32 (s, 1H); 7.62 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.4 Hz, 2H);7.12-7.22 (m, 2H); 6.90-7.00 (m, 1H); 6.50-6.60 (m, 1H); 3.75 (s, 3H);2.62 (q, J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 88N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 78A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.18 (s, 1H); 9.06 (s,1H); 8.32 (s, 1H); 8.02 (s, 1H); 7.50-7.70 (m, 4H); 7.32 (d, J=8.4 Hz,3H); 2.62 (q, J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 89N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methoxyphenyl)urea

The desired product was prepared by substituting Example 78A and2-methoxyphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR(DMSO-d₆) δ 9.58 (s, 1H); 8.30 (s,2H); 8.17 (dd, J=9.0, 1.5 Hz, 1H); 7.62 (d, J=8.4 Hz, 2H); 7.32 (d,J=8.4 Hz, 2H); 6.80-7.10 (m, 3H); 3.92 (s, 3H); 2.62 (q, J=7.5 Hz, 2H);1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 90N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 78A and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.04 (s, 1H); 9.01 (s,1H); 8.35 (s, 1H); 7.88 (t, J=1.8 Hz, 1H); 7.62 (d, J=8.4 Hz, 2H);7.10-7.40 (m, 5H); 2.62 (q, J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 91N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 78A and4-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. ¹H NMR (DMSO-d₆) δ 9.22 (s, 1H); 9.03 (s,1H); 8.35 (s,1H); 7.60-7.80 (m, 6H); 7.37 (d, J=8.4 Hz, 2H); 2.62 (q,J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 925-[4-(1,3-benzoxazol-2-ylamino)phenyl]-6-ethylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 78A for Example1E in Example 3. ¹H NMR (DMSO-d₆) δ 10.90 (s, 1H); 8.28 (s, 1H); 7.96(d, J=8.4 Hz, 2H); 7.50 (dd, J=12, 7.4 Hz, 2H); 7.42 (d, J=8.4 Hz, 2H);7.10-7.30 (m, 2H); 2.62(q, J=7.5 Hz, 2H); 1.98 (t, J=7.5 Hz, 3H).

EXAMPLE 93N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzamide

The desired product was prepared by substituting Example 78A for Example1E in Example 4. m.p. 213-214° C.; ¹H NMR (DMSO-d₆) δ 10.46 (s, 1H);8.26 (s, 1H); 7.98 (d, J=8.4 Hz, 4H); 7.50-7.70 (m, 3H); 7.40 (d, J=8.4Hz, 2H); 2.66 (q, J=7.5 Hz, 2H); 1.17 (t, J=7.5 Hz, 3H).

EXAMPLE 94N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]benzenesulfonamide

The desired product was prepared by substituting Example 78A for Example1E in Example 2. m.p. 209-210° C.; ¹H NMR (DMSO-d₆) δ 10.44 (s, 1H);8.22 (s, 1H); 7.70-7.80 (m, 2H); 7.50-7.70 (m, 3H); 7.10-7.30 (m, 4H);2.56 (q, J=7.5 Hz, 2H); 1.04 (t, J=7.5 Hz, 3H).

EXAMPLE 95N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-2-(3-methylphenyl)acetamide

The desired product was prepared by substituting Example 78A and3-methylphenylacetyl chloride for Example 1E and benzoyl chloride,respectively, in Example 4. ¹H NMR (DMSO-d₆) 10.36 (s, 1H); 8.26 (s,1H); 7.78 (d, J=9.0 Hz, 2H); 7.33 (d, J=9.0 Hz, 2H); 7.00-7.30 (m, 4H);3.63 (s, 2H); 2.62 (q, J=7.5 Hz, 2H); 2.31 (s, 3H); 1.14 (t, J=7.5 Hz,3H).

EXAMPLE 96 3-(4-nitrophenyl)isothiazolo[5,4-d]pyrimidin-4-amine EXAMPLE96A 2-[hydroxy(4-nitrophenyl)methylene]malononitrile

A 0° C. solution of 4-nitrobenzoyl chloride (24.12 g, 130 mmol) andmalononitrile (8.60 g, 130 mmol) in dichloromethane (200 mL) was treatedwith PhCH₂N(CH₂CH₃)₃Cl (3.0 g), treated dropwise with 10N NaOH (30 mL),stirred at 0° C. for 1 hour, and filtered. The filter cake was washedwith dichloromethane and diethyl ether, dissolved in 5% HCl, andextracted with ethyl acetate. The extract was dried (MgSO₄), filtered,and concentrated. The concentrate was recrystallized from ethylacetate/hexanes to provide 23 g of the desired product. MS(ESI(−)) m/e214 (M−H)⁻.

EXAMPLE 96B 2-[chloro(4-nitrophenyl)methylene]malononitrile

A mixture of PCl₅ (16.6 g, 80 mmol) in dichloromethane (500 mL) wasadded dropwise to a suspension of Example 96A (8.6 g, 40 mmol) indichloromethane (80 mL). The resulting mixture was heated to reflux for20 hours, cooled to room temperature, and concentrated. The residue wasdissolved in a minimal amount of dichloromethane and filtered through aplug of silica gel. The plug was washed with dichloromethane and thefiltrate was concentrated. The concentrate was recrystallized fromdichloromethane/hexanes to provide 5.4 g (57% yield) of the desiredproduct. R_(f)=0.7 (5% methanol/dichloromethane).

EXAMPLE 96C 2-[amino(4-nitrophenyl)methylene]malononitrile

A suspension of Example 96B (5.4 g) in ethanol (100 mL) at roomtemperature was treated dropwise with concentrated NH₄OH (100 mL),stirred for 4 hours, poured into ice water, and filtered. The filtercake was dried to provide 4.7 g (93% yield) the desired product.MS(ESI(−)) m/e 213 (M−H)⁻.

EXAMPLE 96D (2Z)-3-amino-2-cyano-3-(4-nitrophenyl)prop-2-enethioamide

A suspension of Example 96C (2.1 g, 9.8 mmol) and 90% diethyldithiophosphate (1.8 mL, 10.8 mmol) in ethanol (15 mL) and water (15 mL)was heated to reflux for 24 hours, cooled to room temperature, pouredinto ice water (300 mL), and filtered. The filter cake was dried toprovide 2.3 g (95% yield) of the desired product. MS(ESI(−)) m/e 247(M−H)⁻.

EXAMPLE 96E 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile

A suspension of Example 96D (23 g, 9.26 mmol) in ethanol (100 mL) wastreated with 31% H₂O₂ (2 mL, 1.85 mmol), stirred at room temperatureovernight, poured into ice water, and filtered. The filter cake waswashed with water and dried to provide 2.2 g (96% yield) of the desiredproduct. MS(ESI(−)) m/e 245 (M−H)⁻.

EXAMPLE 96F 3-(4-nitrophenyl)isothiazolo[5,4-d]pyrimidin-4-amine

A mixture of Example 96E (200 mg) in formamide (5 mL) in a capped vialwas heated to 210° C. in a Smith microwave oven at 300 W for 25 minutes,poured into water, and filtered. The filter cake was dried to provide2.02 g (84% yield) of the desired product. MS(ESI(+)) m/e 274 (M+H)⁺.

EXAMPLE 97 3-(4-aminophenyl)isothiazolo[5,4-d]pyrimidin-4-amine

A mixture of Example 96F (0.95 g, 3.5 mmol), iron (0.78 g, 13.9 mmol),and NH₄Cl (0.19 g, 3.5 mmol) in 9:1 ethanol/water (80 mL) was heated to60° C. for 4 hours, cooled to room temperature, and filtered through apad of diatomaceous earth (Celite®). The pad was washed with THF and thefiltrate was concentrated. The concentrate was suspended in water andfiltered. The filter cake was washed with water and dried to provide0.82 g (97% yield) of the desired product.

EXAMPLE 98N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 97 and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(−)) m/e 429 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 9.18 (s, 1H); 9.12 (s, 1H); 8.46 (s, 1H); 8.04 (s, 1H); 7.50-7.80 (m,6H); 7.35 (d, 1H, J=8.4 Hz).

EXAMPLE 99N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 97 and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(−)) m/e 375 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 8.80 (s, 1H); 8.65 (s, 1H); 8.44 (s, 1H); 7.50-7.80 (m, 4H); 7.10-7.40(m, 3H). 6.80 (d, J=8.4 Hz, 1H); 2.28 (s, 3H).

EXAMPLE 100N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 97 and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(−)) m/e 395 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 9.08 (s, 1H); 9.00 (s, 1H); 8.42 (s, 1H); 7.50-8.00 (m, 5H); 7.20-7.40(m, 2H); 7.00-7.10 (m, 1H).

EXAMPLE 101N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 97 and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+) m/e 391 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 8.98 (s, 1H); 8.72 (s, 1H); 8.45 (s, 1H); 7.50-7.80 (m, 4H); 7.10-7.40(m, 3H); 6.84 (d, 1H); 2.58 (q, J=7.2 Hz, 2H); 1.18 (t, J=7.2 Hz, 3H);Anal. Calcd. for C₂₀H₁₈N₆OS.0.7H₂O: C, 59.60; H, 4.85; N, 20.85. Found:C, 60.07; H, 4.65; N, 20.34.

EXAMPLE 102 3-(4-phenoxyphenyl)isothiazolo[5,4-d]pyrimidin-4-amineEXAMPLE 102A 2-[amino(4-phenoxyphenyl)methylene]malononitrile

The desired product was prepared by substituting 4-phenoxybenzoylchloride for 4-nitrobenzoyl chloride in Examples 96A-C.

EXAMPLE 102B (2E)-3-amino-2-cyano-3-(4-phenoxyphenyl)prop-2-enethioamide

A solution of Example 102A (1.6 g, 6.12 mmol) in pyridine (10 mL) wastreated with triethylamine (0.76 mL, 5.5 mmol) and heated to 80° C. H₂Sgas was bubbled through the solution for 4 hours, the mixture was cooledto room temperature, and partitioned between water and ethyl acetate.The organic phase was dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 5% ethyl acetate/hexanes to provide 1.4 g (77% yield) of thedesired product. MS(DCI/NH₃) m/e 296 (M+H)⁺.

EXAMPLE 102C 3-(4-phenoxyphenyl)isothiazolo[5,4-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 102B forExample 96D in Example 96E and Example 96F. MS(ESI(+)) m/e 321 (M+H)⁺;¹H NMR (DMSO-d₆) δ 8.45 (s, 1H); 7.60-7.70 (m,2H); 7.40-7.50 (m, 2H);7.10-7.30 (m, 5H).

EXAMPLE 103N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 97 and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 449 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 9.44 (s,1H); 9.00 (d, J=3 Hz, 1H); 9.63 (dd, J=7.2, 2.0Hz, 1H); 8.47 (s, 1H); 7.30-7.80 (m, 6H).

EXAMPLE 104N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)ureaEXAMPLE 104A4-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-nitrophenyl)butan-1-one

A mixture of Zn—Cu couple (2.68 g, 41.3 mmol) andtert-butyl(3-iodopropoxy)dimethylsilane (8.26 g, 27.5 mmol) in benzene(55 mL) and DMF (3.6 mL) was stirred vigorously at room temperature for1 hour, heated to 60° C. for 4 hours, cooled to room temperature, andtreated with a solution of 4-nitrobenzoyl chloride (3.4 g, 18.3 mmol)and (Ph₃P)₄Pd (0.847 g, 0.73 mmol) in benzene (36 mL) by cannula. Themixture was stirred for 1 hour, filtered through diatomaceous earth(Celite®), and partitioned between saturated NH₄Cl and ethyl acetate.The aqueous phase was extracted three times with ethyl acetate and thecombined extracts were washed with water and brine, dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% ethyl acetate/hexanes to provide2.81 g of the desired product. MS(ESI(−)) m/e 322 (M−H)⁻.

EXAMPLE 104B5-(4-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 104A forExample 1A in Examples 1B-1E.

EXAMPLE 104CN-{4-[4-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 104B and3-methylphenyl isocyanate for phenyl isocyanate and Example 1E,respectively, in Example 1F.

EXAMPLE 104DN-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

A solution of Example 104C (92 mg, 0.17 mmol) in THF (5 mL) at roomtemperature was treated dropwise with a solution of 1M TBAF in THF (0.3mL, 0.3 mmol), stirred overnight, and partitioned between water andethyl acetate. The aqueous phase was extracted three times with ethylacetate and the combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The concentrate was recrystallized from dichloromethane toprovide 54 mg (75%) of the desired product. MS(ESI) m/e 420 (M+H)⁺, 418(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 2.75-2.80 (t, J=6.6Hz, 2H); 3.54-3.60 (m, 2H); 4.85-4.89 (t, J=5.7 Hz, 1H); 6.79-6.82 (d,J=7.5 Hz, 2H); 7.14-7.19 (t, J=7.5 Hz, 1H); 7.24-7.32 (m, 4H); 7.61-7.63(d, J=8.4 Hz, 2H); 8.26 (s, 1H); 8.67 (s, 1H); 8.87 (s, 1H); Anal.Calcd. for C₂₂H₂₁N₅O₂S.0.4H₂O: C, 61.93; H, 5.15; N, 16.41. Found: C,61.80; H, 4.95; N, 16.31.

EXAMPLE 105N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 104B and4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F, then substituting the product for Example104C in Example 104D. MS(ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.25 (s, 3H); 2.75-2.80 (m, 2H); 3.52-3.63 (m, 2H); 4.53-4.54(m, 1H); 7.08-7.11 (d, J=7.8 Hz, 2H); 7.29-7.32 (d, J=8.7 Hz, 2H);7.34-7.37 (d, J=8.1 Hz, 2H); 7.60-7.63 (d, J=8.4 Hz, 2H); 8.26 (s, 1H);8.64 (s, 1H); 8.84 (s, 1H).

EXAMPLE 106N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 104B and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F, then substituting the resulting product forExample 104C in Example 104D. MS(ESI(+)) m/e 440, 442 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.74-2.79 (t, J=6.3 Hz, 2H); 3.54-3.60 (m, 2H);4.86-4.89 (t, J=5.1 Hz, 1H); 7.02-7.05 (td, J=2.4, 6.3 Hz, 1H);7.30-7.35 (m, 4H); 7.61-7.64 (d, J=8.4 Hz, 2H); 7.73-7.74 (m, 1H); 8.27(s, 1H); 8.98 (s, 2H).

EXAMPLE 107N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(2-methylphenyl)urea

The desired product was prepared by substituting Example 104B and2-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F, then substituting the resulting product forExample 104C in Example 104D. m.p. 159-162° C.; MS(ESI(+)) m/e 420(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (s, 3H); 2.75-2.79 (t, J=6.9Hz, 2H); 3.54-3.60 (m, 2H); 4.86-4.89 (t, J=5.4 Hz, 1H); 6.94-6.99 (t,J=7.2 Hz, 1H); 7.13-7.21 (m, 2H); 7.29-7.33 (d, J=9 Hz, 2H); 7.62-7.65(d, J=8.4 Hz, 2H); 7.81-7.83 (d, J=9.2 Hz, 1H); 8.01 (s, 1H); 8.26 (s,1H); 9.23 (s, 1H).

EXAMPLE 1085-(4-aminophenyl)-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 1-iodo-3-methoxypropanefor tert-butyl(3-iodopropoxy)dimethylsilane in Examples 104A and 104B.m.p. 144-146° C.

EXAMPLE 109N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 108 and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 434 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H); 2.83-2.87 (t, J=6.6 Hz, 2H); 3.22 (s, 3H);3.47-3.52 (t, J=6.6 Hz, 2H); 6.79-6.82 (d, J=7.5 Hz, 2H); 7.14-7.19 (t,J=7.5 Hz, 1H); 7.24-7.32 (m, 4H); 7.61-7.64 (d, J=9 Hz, 2H); 8.27 (s,1H); 8.67 (s, 1H); 8.87 (s, 1H).

EXAMPLE 110N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 108 and4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 128-132° C.; MS(ESI(+)) m/e 434(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 3H); 2.83-2.87 (t, J=6.6Hz, 2H); 3.22 (s, 3H); 3.47-3.52 (t, J=6.6 Hz, 2H); 7.09-7.11 (d, J=8.1Hz, 2H); 7.28-7.32 (d, J=8.4 Hz, 2H); 7.34-7.37 (d, J=8.4 Hz, 2H);7.60-7.63 (d, J=9 Hz, 2H); 8.27 (s, 1H); 8.64 (s, 1H); 8.84 (s, 1H).

EXAMPLE 111N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}benzenesulfonamide

The desired product was prepared by substituting Example 108 for Example1E in Example 2. m.p. 206-208° C.; MS(ESI(+)) m/e 441 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.72-2.76 (t, J=6.3 Hz, 2H); 3.14 (s, 3H);3.39-3.44 (t, J=6.6 Hz, 2H); 7.19-7.28 (m, 4H); 7.57-7.59 (m, 3H);7.74-7.77 (d, J=6.9 Hz, 2H); 8.26 (s, 1H); 10.49 (s, 1H).

EXAMPLE 112N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-2-(3-methylphenyl)acetamide

The desired product was prepared by substituting Example 108 and3-methylphenylacetyl chloride for Example 1E and benzoyl chloride,respectively, in Example 4. m.p. 200-202° C.; MS(ESI(+)) m/e 433 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H); 2.80-2.84 (t, J=6.6 Hz, 2H);3.21 (s, 3H); 3.45-3.49 (t, J=6.6 Hz, 2H); 3.64 (s, 2H); 7.06-7.08 (d,J=7.5 Hz, 1H); 7.13-7.25 (m, 3H); 7.31-7.34 (d, J=8.4 Hz, 2H); 7.75-7.78(d, J=9 Hz, 2H); 8.26 (s, 1H); 10.36 (s, 1H).

EXAMPLE 113N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}benzamide

The desired product was prepared by substituting Example 108 for Example1E in Example 4. m.p. 200-202° C.; MS(ESI(+)) m/e 405 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.84-2.88 (t, J=6.3 Hz, 2H); 3.23 (s, 3H);3.48-3.53 (d, J=6.3 Hz, 2H); 7.38-7.41 (d, J=8.4 Hz, 2H); 7.54-7.62 (m,3H); 7.96-7.99 (m, 4H); 8.28 (s, 1H); 10.47 (s, 1H); Anal. Calcd. forC₂₂H₂₀N₄O₂S.0.4H₂O: C, 64.18; H, 5.09; N, 13.61. Found: C, 64.28; H,4.96; N, 13.34.

EXAMPLE 114N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 108 and3-(trifluoromethyl)phenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 488 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.83-2.87 (t, J=6.3 Hz, 2H); 3.22 (s, 3H);3.48-3.52 (d, J=6.3 Hz, 2H); 7.31-7.34 (d, J=9 Hz, 3H); 7.51-7.56 (t,J=8.1 Hz, 1H); 7.62-7.67 (m, 3H); 8.04 (s, 1H); 8.27 (s, 1H); 9.02 (s,1H); 9.14 (s, 1H); Anal. Calcd. for C₂₃H₂₀N₅O₂SF₃: C, 56.67; H, 4.13; N,14.37. Found: C, 56.40; H, 4.18; N, 14.15.

EXAMPLE 115N-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)ureaEXAMPLE 115A 1-(4-nitrophenyl)-3-pyridin-3-ylpropan-1-one

The desired product was prepared by substituting3-pyridinecarboxaldehyde for 4-pyridinecarboxaldehyde in Example 14A,then substituting the resulting product for Example 14A in Example 14B.MS(ESI(+)) m/e 257 (M+H)⁺.

EXAMPLE 115BN-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 115A and3-methylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 467 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.04 (s, 2H); 6.79-6.82 (d, J=7.5 Hz, 1H);7.14-7.19 (t, J=7.8 Hz, 1H); 7.24-7.33 (m, 3H); 7.35-7.37 (d, J=8.4 Hz,2H); 7.53-7.56 (td, J=2.1 Hz, 7.8 Hz, 1H); 7.63-7.66 (d, J=8.4 Hz, 2H);8.27 (s, 1H); 8.34-8.35 (d, J=1.8 Hz, 1H); 8.42-8.44 (dd, J=1.5, 4.8 Hz,1H); 8.67 (s, 1H); 8.89 (s, 1H); Anal. Calcd. for C₂₆H₂₂N₆OS.0.2H₂O: C,66.42; H, 4.80; N, 17.87. Found: C, 66.38; H, 4.80; N, 17.92.

EXAMPLE 116N-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 115A and4-methylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. mp: 220-223° C.; MS(ESI(+)) m/e 467(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 3H); 4.04 (s, 2H);7.08-7.11 (d, J=8.1 Hz, 2H); 7.29-7.37 (m, 5H); 7.52-7.56 (td, J=2.1,7.8 Hz, 1H); 7.62-7.65 (d, J=8.7 Hz, 2H); 8.27 (s, 1H); 8.34-8.35 (d,J=2.1 Hz, 1H); 8.41-8.43 (dd, J=1.2, 4.5 Hz, 1H); 8.64 (s, 1H); 8.86 (s,1H); Anal. Calcd. for C₂₆H₂₂N₆OS: C, 66.93; H, 4.75; N, 18.01. Found: C,66.69; H, 4.65; N, 18.05.

EXAMPLE 117N-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 115A and3-chlorophenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. m.p. 169-172° C.; MS(ESI(+)) m/e 487(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.02-7.06 (td, 1H,J=2.4, 6.6 Hz); 7.29-7.35(m, 3H); 7.36-7.39 (d, 2H, J=8.7 Hz); 7.52-7.56(td, 1H, J=1.8, 7.8 Hz); 7.64-7.67 (d, 2H, J=8.7 Hz); 7.72-7.73 (m, 1H);8.27 (s, 1H); 8.34-8.35 (d, 1H, J=2.4 Hz); 8.41-8.44 (dd, 1H, J=1.5, 4.8Hz); 8.97 (s, 1H); 8.99 (s, 1H); Anal. Calcd. for C₂₅H₁₉N₆OSCl 0.4H₂O:C, 60.76; H, 4.04; N, 17.01. Found: C, 60.81; H, 4.04; N, 16.77.

EXAMPLE 118N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting 3-fluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 394(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (s, 1H); 8.97 (s, 1H); 8.27 (s,1H); 7.64 (d, J=8.4 Hz, 2H); 7.51 (dt, J=12.0 Hz, 2.1 Hz, 1H); 7.36-7.28(m, 3H); 7.15 (d, J=8.1 Hz, 1H); 6.80 (td, J=8.1 Hz, 2.4 Hz); 2.30 (s,3H).

EXAMPLE 119N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting 4-fluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 394(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (s, 1H); 8.79 (s, 1H); 8.26 (s,1H); 7.63 (d, J=8.4 Hz, 2H); 7.51-7.46 (m, 2H); 7.31 (d, J=8.4 Hz, 2H);7.14 (t, J=9.0 Hz, 2H); 2.29 (s, 3H).

EXAMPLE 120N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-difluorophenyl)urea

The desired product was prepared by substituting 3,5-difluorophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 412(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (s, 1H); 9.07 (s, 1H); 8.27 (s,1H); 7.64 (d, J=8.7 Hz, 2H); 7.33 (d, J=8.7 Hz, 2H); 7.22 (dd, J=9.9 Hz,2.4 Hz, 2H); 6.81 (tt, J=9.3 Hz, 2.4 Hz); 2.29 (s, 3H).

EXAMPLE 121N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-phenoxyphenyl)urea

The desired product was prepared by substituting 3-phenoxyphenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 466(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H); 8.86 (s, 1H); 8.26 (s,1H); 7.60 (d, J=9.0 Hz, 2H); 7.41 (t, J=8.1 Hz, 2H); 7.32-7.26 (m, 4H);7.16 (t, J=7.5 Hz, 2H); 7.05 (d, J=7.5 Hz, 2H); 6.63 (dd, J=8.1 Hz, 2.4Hz, 1H); 2.29 (s, 3H).

EXAMPLE 122N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-phenoxyphenyl)urea

The desired product was prepared by substituting Example 58D and3-phenoxyphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 454 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.88 (s, 1H); 8.87 (s, 1H); 8.33 (s, 1H); 7.58 (d, J=8.4 Hz,2H); 7.44-7.36 (m, 5H); 7.32-7.26 (m, 2H); 7.20-7.12 (m, 2H); 7.07-7.03(m, 2H); 6.65-6.61 (m, 1H).

EXAMPLE 123N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting 3-cyanophenylisocyanate for phenyl isocyanate in Example 1F. MS(ESI(+)) m/e 401(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H); 9.06 (s, 1H); 8.27 (s,1H); 8.00 (s, 1H); 7.70 (d, J=8.1 Hz, 1H); 7.65 (d, J=8.4 Hz, 2H); 7.52(t, J=8.1 Hz, 1H); 7.44 (d, J=8.1 Hz, 2H); 7.33 (d, J=8.4 Hz, 2H); 2.30(s, 3H).

EXAMPLE 124N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting4-(trifluoromethyl)phenyl isocyanate for phenyl isocyanate in Example1F. MS(ESI(+)) m/e 444 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H);9.02 (s, 1H); 8.27 (s, 1H); 7.71-7.63 (m, 6H); 7.33 (d, J=8.7 Hz, 2H);2.30 (s, 3H).

EXAMPLE 125N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 58D and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 396 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.96 (s, 1H); 8.34 (s, 1H); 7.73 (s, 1H); 7.61 (d, J=8.4 Hz,2H); 7.44 (s, 1H); 7.40 (d, J=8.4 Hz, 2H); 7.32-7.28 (m, 2H); 7.03 (dt,J=2.1 Hz, 1H).

EXAMPLE 126N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 58D and3-(trifluoromethyl)phenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 428 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H); 9.06 (s, 1H); 8.36 (s, 1H); 8.03(s, 1H); 7.65-7.58 (m, 3H); 7.53 (t, J=7.8 Hz, 1H); 7.46 (s, 1H); 7.41(d, J=8.4 Hz, 2H); 7.33 (d, J=7.8 Hz, 1H).

EXAMPLE 127N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 58D (0.04 g, 0.165 mmol) in dichloromethane (3mL) under nitrogen was cooled to 0° C., treated with1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.024 mL, 0.165 mmol),and stirred overnight while gradually warming to room temperature. Thesuspension was filtered and the filter cake was dried in a vacuum ovento provide 0.056 g of the desired product. MS(ESI(+)) m/e 448 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 9.40 (s, 1H); 8.98 (d, J=2.7 Hz, 1H); 8.63 (dd,J=7.2 Hz, 2.1 Hz, 1H); 8.35 (s, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.55-7.39(m, 5H).

EXAMPLE 128N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 61B and2-fluoro-5-(trifluoromethyl)phenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 526, 528 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 1H); 9.00 (d, J=2.7 Hz, 1H); 8.63(dd, J=7.5 Hz, 2.1 Hz, 1H); 8.33 (s, 1H); 7.68 (d, J=8.7 Hz, 2H); 7.52(t, J=8.7 Hz, 1H); 7.45-7.37 (m, 3H).

EXAMPLE 129N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 61B and3-(trifluoromethyl)phenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 508, 510 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H); 9.06 (s, 1H); 8.33 (s, 1H);8.04 (s, 1H); 7.68 (d, J=8.7 Hz, 2H); 7.61 (d, J=8.1 Hz, 1H); 7.53 (t,J=8.1 Hz, 1H); 7.38 (d, J=8.7 Hz, 2H); 7.33 (d, J=8.1 Hz, 1H).

EXAMPLE 130N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 61B and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 474, 476 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 9.02 (s, 1H); 8.99 (s, 1H); 8.33 (s, 1H); 7.73 (s, 1H);7.66 (d, J=8.7 Hz, 2H); 7.37 (d, J=8.7 Hz, 2H); 7.33-7.30 (m, 2H); 7.04(dt, J=6.6 Hz, 2.4 Hz, 1H).

EXAMPLE 131N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-1H-indole-2-carboxamide

The desired compound was prepared by substituting 1H-indole-2-carbonylchloride for benzoyl chloride in Example 4. MS(ESI(+)) m/e 400 (M+H)⁺;¹H NMR(300 MHz, DMSO-d₆) δ 11.80 (s, 1H); 10.40 (s, 1H); 8.28 (s, 1H);8.01 (d, J=8.7 Hz, 2H); 7.70 (d, J=7.5 Hz, 1H); 7.48 (d, J=7.5 Hz, 2H);7.42 (d, J=8.7 Hz, 2H); 7.24 (t, J=7.5 Hz, 1H); 7.08 (t, J=7.5 Hz, 1H);2.32 (s, 3H).

EXAMPLE 132 phenylN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-cyanoimidocarbamate

A solution of Example 1E (0.4 g, 1.56 mmol) and diphenylcyanocarbonimidate (0.372 g, 1.56 mmol) in DMF (10 mL) was heated to 90°C. for 2 days, cooled to room temperature, quenched with water, andfiltered. The filter cake was suspended in ethanol and filtered. Thefiltrate was concentrated and purified by flash column chromatography onsilica gel with 5 to 8% methanol/dichloromethane to provide the desiredproduct (150 mg). MS(ESI(+)) m/e 401(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.06 (s, 1H); 8.27 (s, 1H); 7.67 (d, J=8.4 Hz, 2H); 7.50-7.43 (m, 4H);7.36-7.29 (m, 3H); 2.29 (s, 3H).

EXAMPLE 133N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N″-cyano-N′-(3-methylphenyl)guanidine

A solution of Example 132 (40 mg, 0.01 mmol) and 3-methylaniline (0.012mL, 0.01 mmol) in DMF (1 mL) was heated in a Smith synthesizer microwaveto 180° C. for 22 minutes and partitioned between water and ethylacetate. The aqueous phase was extracted three times with ethyl acetateand the combined extracts were washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The concentrate was purified byflash column chromatography on silica gel with 8%methanol/dichloromethane to provide the desired product (15 mg).MS(ESI(+)) m/e 414 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.65 (s, 1H);9.48 (s, 1H); 8.26 (s, 1H); 7.45 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz,2H); 7.23 (t, J=7.8 Hz, 1H); 7.15-7.10 (m, 2H); 6.96 (d, J=7.8 Hz, 1H);2.29 (s, 6H).

EXAMPLE 134N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N-methyl-N′-(3-methylphenyl)ureaEXAMPLE 134A6-methyl-5-[4-(methylamino)phenyl]thieno[2,3-d]pyrimidin-4-amine

A −20° C. suspension of Example 1E (400 mg, 1.56 mmol) indichloromethane (10 mL) and THF (10 mL) was treated with formic aceticanhydride (0.135 mL, 1.7 mmol), stirred for 1 hour, and concentrated.The concentrate was suspened in benzene (50 mL), treated with 65% Red-Alin toluene (2.4 mL, 7.8 mmol), stirred at room temperature for 20minutes than heated to reflux for 6 hours. The reaction was cooled toroom temperature and partitioned between Rochelle's salt and ethylacetate. The aqueous phase was extracted three times with ethyl acetateand the combined extracts were washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 7%methanol/dichloromethane to provide the desired product (86 mg).MS(ESI(+)) m/e 271 (M+H)⁺.

EXAMPLE 134BN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N-methyl-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 134A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 404 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 8.32 (s, 1H); 8.28 (s, 1H); 7.47 (d, J=8.4 Hz, 2H); 7.40 (d,J=8.4 Hz, 2H); 7.29-7.23 (m, 2H); 7.12 (t, J=7.8 Hz, 1H); 6.78 (d, J=7.8Hz, 1H); 3.33 (s, 3H); 2.33 (s, 3H); 2.25 (s, 3H).

EXAMPLE 135N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N-methyl-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 134A and3-(trifluoromethyl)phenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS(ESI(+)) m/e 458 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 8.73 (s, 1H); 8.28 (s, 1H); 7.97 (s, 1H); 7.69(d, J=7.5 Hz, 1H); 7.53-7.40 (m, 5H); 7.30 (d, J=7.5 Hz, 1H); 2.33 (s,3H).

EXAMPLE 136N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)thiourea

A solution of Example 1E (60 mg, 0.23 mmol) and 3-methylphenylisothiocyanate in DMF (2 mL) was stirred at room temperature. for 48hours, quenched with water, and filtered. The filter cake was dried toprovide the desired product (75 mg, 80%). MS(ESI(+)) m/e 406 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H); 9.84 (s, 1H); 8.27 (s, 1H); 7.65(d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.30-7.18 (m, 3H); 6.97 (d,J=6.9 Hz, 1H); 2.30 (s, 6H).

EXAMPLE 137N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(2-methylphenyl)urea

The desired product was prepared by substituting Example 108 and2-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. m.p. 217-219° C.; MS(ESI(+)) m/e 434(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (s, 3H); 2.83-2.87 (t, J=6.6Hz, 2H); 3.22 (s, 3H); 3.48-3.52 (t, J=6.6 Hz, 2H); 6.95-6.99 (t, J=7.5Hz, 1H); 7.14-7.21 (m, 2H); 7.29-7.32 (d, J=8.7 Hz, 2H); 7.63-7.65 (d,J=8.7 Hz, 2H); 7.81-7.83 (d, J=8.1 Hz, 1H); 8.01 (s, 1H); 8.27 (s, 1H);9.23 (s, 1H).

EXAMPLE 138N-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 115A and3-trifluoromethylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 521 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.29-7.34 (m, 2H); 7.37-7.39 (d, 2H, J=8.4Hz); 7.50-7.62 (m, 3H); 7.65-7.68 (d, 2H, J=8.7 Hz); 8.03 (s, 1H); 8.28(s, 1H); 8.34-8.35 (d, 1H, J=2.1 Hz); 8.42-8.44 (dd, 1H, J=1.5, 4.8 Hz);9.05 (s, 1H); 9.15 (s, 1H).

EXAMPLE 139N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 104B and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F, then substituting the resulting product forExample 104C in Example 104D. m.p. 155-158° C.; MS(ESI(+)) m/e 474(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.75-2.79 (t, J=6.9 Hz, 2H);3.56-3.57 (m, 2H); 4.85-4.90 (m, 1H); 7.32-7.34 (d, J=8.7 Hz, 3H);7.50-7.59 (m 2H); 7.62-7.65 (d, J=9 Hz, 2H); 8.03 (s, 1H); 8.27 (s, 1H);9.03 (s, 1H); 9.15 (s, 1H).

EXAMPLE 140N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 108 and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. m.p. 209-211° C.; MS(ESI(+))m/e 506 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.83-2.87 (t, J=6 Hz, 2H);3.22 (s, 3H); 3.48-3.52 (t, J=6.3 Hz, 2H); 7.33-7.36 (d, J=8.7 Hz, 2H);7.40-7.55 (m, 2H); 7.63-7.66 (d, J=8.4 Hz, 2H); 8.27 (s, 1H); 8.62-8.65(dd, J=2.1, 6.9 Hz, 1H); 8.98-8.99 (d, J=2.7 Hz, 1H); 9.39 (s, 1H).

EXAMPLE 141N-{4-[4-amino-6-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 115A and3-trifluoromethylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 539 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.29-7.33 (m, 1H); 7.38-7.44 (m, 3H),7.48-7.57 (m, 2H); 7.65-7.68 (d, J=8.7 Hz, 2H); 8.28 (s, 1H);8.34-8.35(d, J=1.8 Hz, 1H); 8.42-8.44 (dd, J=1.8, 4.8 Hz, 1H); 8.62-8.65(dd, J=2.4, 7.5 Hz, 1H); 8.98-8.99 (d, J=2.7 Hz, 1H); 9.41 (s, 1H).

EXAMPLE 142N-{4-[4-amino-6-(pyridin-4-ylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 14B and3-trifluoromethylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. m.p. 162-166° C.; MS(ESI(+)) m/e 521(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.15-7.16 (m, 2H);7.32-7.37 (m, 3H), 7.50-7.66 (m, 4H); 8.03 (s, 1H); 8.29 (s, 1H);8.38-8.54 (m, 2H); 9.03 (s, 1H); 9.14 (s, 1H).

EXAMPLE 143N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-methylphenyl)ureaEXAMPLE 143A 5-(3-chlorophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting1-(3-chlorophenyl)propan-1-one for Example 1A in Examples 1B-1D.MS(ESI(+)) m/e 276, 278 (M+H)⁺.

EXAMPLE 143B5-(3-chloro-4-nitrophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

A 0° C. suspension of Example 143A (2.13 g, 7.74 mmol) in concentratedH₂SO₄ (15 mL) was treated dropwise over 3 minutes with a solution offuming nitric acid (0.38 mL) in concentrated H₂SO₄ (5 mL). The mixturewas stirred for 30 minutes while warming to room temperature, pouredonto ice, adjusted to pH 7 with solid Na₂CO₃, and extracted with ethylacetate. The extract was dried (MgSO₄), filtered, and concentrated toprovide 2.31 g (93% yield) of the desired product. MS(ESI(+)) m/e 321(M+H)⁺.

EXAMPLE 143C5-(4-amino-3-chlorophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 143B forExample 1D in Example 1E. MS(ESI(+)) m/e 276, 278 (M+H)⁺.

EXAMPLE 143DN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 143C and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 424.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 2.31 (s, 3H); 6.83 (d, J=7.5 Hz, 1H); 7.19(t, J=7.5 Hz, 1H); 7.24-7.29 (m, 1H); 7.32-7.34 (m, 2H); 7.53 (d, J=2.0Hz, 1H); 8.27 (s, 1H); 8.37 (d, J=8.5 Hz, 1H); 8.46 (s, 1H); 9.45 (s,1H).

EXAMPLE 144N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 143C and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 438.1 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 2.25 (s, 6H); 2.31 (s, 3H); 6.66 (s, 1H); 7.11 (s, 2H);7.31 (dd, J=8.4, 2.0 Hz, 1H); 7.52 (d, J=2.1 Hz, 1H); 8.28 (s, 1H); 8.37(d, J=8.6 Hz, 1H); 8.44 (s, 1H); 9.37 (s, 1H).

EXAMPLE 145N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 143C and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 496.0 (M+H)⁺;¹H NMR (400 MHz, DMSO-d₆) δ 2.32 (s, 3H); 7.34 (dd, J=8.6, 2.1 Hz, 1H);7.41-7.45 (m, 1H); 7.52 (d, J=10.7 Hz, 1H); 7.55 (d, J=2.1 Hz, 1H); 8.28(s, 1H); 8.35 (d, J=8.3 Hz, 1H); 8.66 (dd, J=7.4, 2.1 Hz, 1H); 9.09 (s,1H); 9.79 (s, 1H).

EXAMPLE 146N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 143C and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 438.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.19 (t, J=7.6 Hz, 3H); 2.31 (s, 3H); 2.60 (q, J=7.6 Hz,2H); 6.87 (d, J=7.1 Hz, 1H); 7.22 (t, J=7.8 Hz, 1H); 7.28-7.37 (m, 3H);7.53 (d, J=2.0 Hz, 1H); 8.27 (s, 1H); 8.37 (d, J=8.5 Hz, 1H); 8.46 (s,1H); 9.47 (s, 1H).

EXAMPLE 147N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 143C and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 478.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 7.34 (dd, J=8.5, 2.0 Hz, 1H); 7.35-7.37(m, 1H); 7.53-7.60 (m, 3H); 8.06 (s, 1H); 8.28 (s, 1H); 8.35 (d, J=8.5Hz, 1H); 8.55 (s, 1H); 9.86 (s, 1H).

EXAMPLE 148N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 143C and4-fluoro-3-trifluromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. ¹H NMR (300 MHz, DMSO-d₆) δ2.31 (s, 3H); 7.34 (dd, J=8.5, 2.0 Hz, 1H); 7.48 (app t, J=9.2 Hz, 1H);7.55 (d, J=2.0 Hz, 1H); 7.64 (ddd, J=8.7, 3.8, 3.0 Hz, 1H); 8.04 (dd,J=6.3, 2.5 Hz, 1H); 8.28 (s, 1H); 8.33 (d, J=8.5 Hz, 1H); 8.53 (s, 1H);9.84 (s, 1H).

EXAMPLE 149N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 143C and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 428.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 6.83 (td, J=8.2, 2.2 Hz, 1H); 7.13 (ddd,J=8.2, 1.9, 0.7 Hz, 1H); 7.31-7.36 (m, 2H); 7.53 (dt, J=12.2, 2.4 Hz,1H); 7.54 (d, J=2.0 Hz, 1H); 8.28 (s, 1H); 8.34 (d, J=8.5 Hz, 1H); 8.53(s, 1H); 9.73 (s, 1H).

EXAMPLE 150N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3,4-dimethylphenyl)urea

The desired product was prepared by substituting Example 143C and3,4-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 438.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.17 (s, 3H); 2.21 (s, 3H); 2.31 (s, 3H); 7.06 (d, J=8.1Hz, 1H); 7.20 (dd, J=8.5, 2.4 Hz, 1H); 7.26 (d, J=2.0 Hz, 1H); 7.31 (dd,J=8.5, 2.0 Hz, 1H); 7.52 (d, J=2.0 Hz, 1H); 8.27 (s, 1H); 8.37 (d, J=8.5Hz, 1H); 8.42 (s, 1H); 9.35 (s, 1H).

EXAMPLE 151N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 143C and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 443.9 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 7.07 (ddd, J=7.7, 2.1, 1.0 Hz, 1H); 7.26(ddd, J=8.3, 2.0, 1.2 Hz, 1H); 7.33 (d, J=8.1 Hz, 1H); 7.35 (dd, J=8.5,5.1 Hz, 1H); 7.54 (d, J=2.0 Hz, 1H); 7.76 (t, J=2.0 Hz, 1H); 8.27 (s,1H); 8.34 (d, J=8.5 Hz, 1H); 8.53 (s, 1H); 9.70 (s, 1H).

EXAMPLE 152N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3-methylphenyl)ureaEXAMPLE 152A5-(4-amino-3-fluorophenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting1-(3-fluorophenyl)propan-1-one for 1-(3-chlorophenyl)propan-1-one) inExamples 143A-C. MS (ESI(+)) m/e 275 (M+H)⁺.

EXAMPLE 152BN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N-(3-methylphenyl)urea

The desired product was prepared by substituting Example 152A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 408.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 2.31 (s, 3H); 6.83 (d, J=7.1 Hz, 1H);7.15-7.37 (m, 5H); 8.27 (s, 1H); 8.35 (t, J=8.5 Hz, 1H); 8.73 (s, 1H);9.08 (s, 1H).

EXAMPLE 153N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 152A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 422.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.25 (s, 6H); 2.31 (s, 3H); 6.65 (s, 1H); 7.09 (s, 2H);7.15 (dd, J=8.3, 1.5 Hz, 1H); 7.34 (dd, J=12.0, 1.9 Hz, 1H); 8.27 (s,1H); 8.35 (t, J=8.5 Hz, 1H); 8.71 (d, J=2.4 Hz, 1H); 9.01 (s, 1H).

EXAMPLE 154N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 152A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 428.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 7.06 (ddd, J=7.8, 2.0, 1.0 Hz, 1H); 7.18(dd, J=8.5, 1.4 Hz, 1H); 7.26 (ddd, J=8.1, 2.0, 1.4 Hz, 1H); 7.31-7.38(m, 2H); 7.75 (t, J=2.0 Hz, 1H); 8.27 (s, 1H); 8.31 (t, J=8.5 Hz, 1H);8.80 (d, J=2.4 Hz, 1H); 9.34 (s, 1H).

EXAMPLE 155N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 152A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 462.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 7.18 (d, J=8.5 Hz, 1H); 7.35-7.39 (m, 2H);7.52-7.56 (m, 2H); 8.06 (s, 1H); 8.27 (s, 1H); 8.31 (t, J=8.5 Hz, 1H);8.83 (s, 1H); 9.49 (s, 1H).

EXAMPLE 156N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3,4-dimethylphenyl)urea

The desired product was prepared by substituting Example 152A and3,4-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 422.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.17 (s, 3H); 2.21 (s, 3H); 2.31 (s, 3H); 7.05 (d, J=8.1Hz, 1H); 7.15 (dd, J=8.7, 1.5 Hz, 1H); 7.19 (dd, J=8.1, 2.0 Hz, 1H);7.25 (d, J=2.0 Hz, 1H); 7.33 (dd, J=11.9, 1.7 Hz, 1H); 8.27 (s, 1H);8.35 (t, J=8.5 Hz, 1H); 8.68 (d, J=2.7 Hz, 1H); 8.98 (s, 1H).

EXAMPLE 157N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 152A and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 422.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.19 (t, J=7.5 Hz, 3H); 2.31 (s, 3H); 2.59 (q, J=7.5 Hz,2H); 6.86 (d, J=7.1 Hz, 1H); 7.16 (dd, J=8.1, 1.7 Hz, 1H); 7.21 (t,J=7.6 Hz, 1H); 7.33-7.35 (m, 1H); 7.34 (dd, J=11.7, 2.2 Hz, 1H); 8.27(s, 1H); 8.35 (t, J=8.7 Hz, 1H); 8.72 (d, J=2.4 Hz, 1H); 9.10 (s, 1H).

EXAMPLE 158N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-phenylurea

The desired product was prepared by substituting Example 152A forExample 1E in Example 1F. MS (ESI(+)) m/e 394.0 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.31 (s, 3H); 7.01 (m, 1H); 7.17 (dd, J=8.3, 1.5 Hz, 1H);7.31 (t, J=8.5 Hz, 2H); 7.35 (dd, J=12.0, 1.9 Hz, 1H); 7.48 (dd, J=7.8,1.0 Hz, 2H); 8.27 (s, 1H); 8.35 (t, J=8.5 Hz, 1H); 8.74 (d, J=2.7 Hz,1H); 9.15 (s, 1H).

EXAMPLE 159N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 152A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 480.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H); 7.18 (dd, J=8.3, 1.5 Hz, 1H);7.38 (dd, J=11.9, 2.0 Hz, 1H); 7.44 (dd, J=4.2, 2.2 Hz, 1H); 7.53 (dd,J=10.9, 8.8 Hz, 1H); 8.27 (s, 1H); 8.36 (t, J=8.7 Hz, 1H); 8.66 (dd,J=7.5, 2.0 Hz, 1H); 9.35 (d, J=2.0 Hz, 1H); 9.46 (d, J=2.7 Hz, 1H).

EXAMPLE 160N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 152A and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 412.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.31 (s, 3H); 6.82 (tdd, J=8.5, 2.7, 0.7 Hz, 1H); 7.12(ddd, J=8.2, 2.0, 0.7 Hz, 1H); 7.17 (ddd, J=8.5, 2.0, 0.7 Hz, 1H);7.30-7.38 (m, 2H); 7.53 (dt, J=11.9, 2.4 Hz, 1H); 8.27 (s, 1H); 8.32 (t,J=8.5 Hz, 1H); 8.79 (d, J=2.7 Hz, 1H); 9.36 (s, 1H).

EXAMPLE 1615-[4-(1,3-benzoxazol-2-ylamino)-3-fluorophenyl]-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 152A forExample 1E in Example 3. MS (ESI(+)) m/e 392.0 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.33 (s, 3H); 7.17 (td, J=7.7, 1.2 Hz, 1H); 7.22-7.31 (m,2H); 7.40 (dd, J=11.7, 1.9 Hz, 1H); 7.50 (d, J=7.1 Hz, 1H); 7.54 (d,J=7.8 Hz, 1H); 8.28 (s, 1H); 8.51 (t, J=8.5 Hz, 1H); 10.66 (s, 1H).

EXAMPLE 162N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methylphenyl]-N′-(3-chlorophenyl)ureaEXAMPLE 162A5-(4-amino-3-methylphenyl)-6-methylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 3-methyl-4-nitrobenzoylchloride for 4-nitrobenzoyl chloride in Examples 1A-1E. MS(ESI(+)) m/e271 (M+H)⁺.

EXAMPLE 162BN-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methylphenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 162A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 424.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 2.32 (s, 3H); 7.04 (ddd, J=7.5, 2.0, 1.4Hz, 1H); 7.19 (dd, J=8.3, 2.2 Hz, 1H); 7.24-7.28 (m, 2H); 7.33 (t, J=7.8Hz, 1H); 7.77 (t, J=2.0 Hz, 1H); 8.06 (d, J=8.1 Hz, 1H); 8.15 (s, 1H);8.26 (s, 1H); 9.33 (s, 1H).

EXAMPLE 163N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methylphenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 162A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 458.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 2.33 (s, 3H); 7.19 (dd, J=8.3, 1.9 Hz,1H); 7.25 (d, J=1.7 Hz, 1H); 7.31-7.34 (m, 1H); 7.53 (t, J=8.1 Hz, 1H);7.58 (dt, J=8.5, 1.7 Hz, 1H); 8.04-8.08 (m, 2H); 8.18 (s, 1H); 8.27 (s,1H); 9.49 (s, 1H).

EXAMPLE 164N-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)-2-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 162A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 476.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H); 2.34 (s, 3H); 7.20 (dd, J=8.5,2.0 Hz, 1H); 7.26 (d, J=2.0 Hz, 1H); 7.40 (ddd, J=8.8, 4.0, 2.4 Hz, 1H);7.52 (dd, J=10.5, 8.8 Hz, 1H); 8.10 (d, J=8.5 Hz, 1H); 8.27 (s, 1H);8.64 (s, 1H); 8.68 (dd, J=7.6, 2.2 Hz, 1H); 9.45 (d, J=2.7 Hz, 1H).

EXAMPLE 165N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3-chlorophenyl)ureaEXAMPLE 165A 1-(3-methoxy-4-nitrophenyl)ethanone

A suspension of MgCl₂ (932 mg, 9.8 mmol) in toluene (13 mL) was treatedwith triethylamine (4.65 mL, 33.4 mmol), dimethyl malonate (1.9 mL, 16.6mmol), stirred for 1.5 hours, and treated portionwise over 30 minuteswith 3-methoxy-4-nitrobenzoyl chloride (3 g, 13.9 mmol). The reactionmixture was stirred for 45 minutes, then carefully treated withconcentrated HCl (4 mL). The layers were separated and the organic phasewas dried (Na₂SO₄), filtered, and concentrated. The residue wasdissolved in DMSO (11.5 mL) and water (0.5 mL), heated to refluxovernight, cooled to room temperature, and partitioned between water andethyl acetate. The organic phase was washed sequentially with saturatedNaHCO₃, water, and brine, dried (MgSO₄), filtered, and concentrated toprovide 1.63 g (60% yield) of the desired product. MS (ESI(−)) m/e 194(M−H)⁻.

EXAMPLE 165B 2-[1-(3-methoxy-4-nitrophenyl)ethylidene]malononitrile

A flask equipped with a condenser and a drying tube was charged withacetic acid (35 mL) and hexamethyldisilazane (11.2 mL, 53.1 mmol). Themixture was stirred while cooling to room temperature, treated withExample 165A (6.89 g, 35.3 mmol) and malononitrile (4.66 g, 70.5 mmol),stirred at 65° C. for 3 hour, cooled to room temperature, stirredovernight, and partitioned between water and toluene. The organic phasewas washed with saturated NaHCO₃, water, brine, dried (MgSO₄), filtered,and concentrated. The concentrate was recrystallized from ethanol toprovide 6.11 g (71% yield) of the desired product. MS (ESI(−)) m/e 242(M−H)⁻.

EXAMPLE 165C 2-amino-4-(3-methoxy-4-nitrophenyl)-3-thiophenecarbonitrile

A solution of Example 165B (6.11 g, 25.1 mmol) in THF (38 mL) wastreated with sulfur powder (305 mg, 25.1 mmol) and a solution of NaHCO₃(422 mg, 5 mmol) in water (12 mL). The suspension was stirred at roomtemperature for 4 hours and filtered to provide 4.71 g (68% yield) ofthe desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 3.98 (s, 3H); 6.85 (s,1H); 7.28 (dd, J=8.53, 1.7 Hz, 1H); 7.40 (s, 2H); 7.48 (d, J=1.7 Hz,1H); 7.97 (d, J=8.5 Hz, 1H).

EXAMPLE 165D 5-(4-amino-3-methoxyphenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 165C forExample 1C in Examples 1D-1E. MS(ESI(+)) m/e 273 (M+H)⁺.

EXAMPLE 165EN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 165D and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 426.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.94 (s, 3H); 7.02 (dd, J=8.3, 2.0 Hz, 1H); 7.03 (ddd,J=7.8, 2.0, 1.3 Hz, 1H); 7.14 (d, J=2.0 Hz, 1H); 7.24 (ddd, J=8.3, 2.0,1.3 Hz, 1H); 7.32 (t, J=7.8 Hz, 1H); 7.47 (s, 1H); 7.75 (t, J=2.0 Hz,1H); 8.27 (d, J=8.1 Hz, 1H); 8.34 (s, 1H); 8.44 (s, 1H); 9.59 (s, 1H).

EXAMPLE 166N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 165D and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 460.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.94 (s, 3H); 7.02 (dd, J=8.3, 1.9 Hz, 1H); 7.15 (d,J=1.7 Hz, 1H); 7.31-7.35 (m, 1H); 7.47 (s, 1H); 7.53-7.56 (m, 2H); 8.05(s, 1H); 8.28 (d, J=8.1 Hz, 1H); 8.34 (s, 1H); 8.46 (s, 1H); 9.75 (s,1H).

EXAMPLE 167N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 165D and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 478.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 3.94 (s, 3H); 7.02 (dd, J=8.3, 1.9 Hz, 1H);7.15 (d, J=1.7 Hz, 1H); 7.39 (m, 1H); 7.51 (m, 2H); 8.28 (d, J=8.5 Hz,1H); 8.34 (s, 1H); 8.68 (dd, J=7.1, 2.0 Hz, 1H); 9.08 (s, 1H); 9.65 (d,J=2.7 Hz, 1H).

EXAMPLE 168N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 165D and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 424.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) d 2.28 (s, 3H); 3.93 (s, 3H); 6.78-6.83 (m, 1H); 7.01 (dd,J=8.3, 1.9 Hz, 1H); 7.07-7.15 (m, 2H); 7.47 (s, 1H); 8.02 (dd, J=8.1,2.0 Hz, 1H); 8.28 (d, J=8.5 Hz, 1H); 8.34 (s, 1H); 8.92 (s, 1H); 9.24(d, J=2.0 Hz, 1H).

EXAMPLE 169N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(4-chloro-3-methylphenyl)urea

The desired product was prepared by substituting Example 165D and4-chloro-3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 440.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.27 (s, 3H); 3.93 (s, 3H); 7.01 (dd, J=8.3, 1.9 Hz,1H); 7.13 (d, J=2.0 Hz, 1H); 7.16 (dd, J=8.1, 2.0 Hz, 1H); 7.26 (d,J=8.5 Hz, 1H); 7.46 (s, 1H); 7.73 (d, J=2.0 Hz, 1H); 8.26 (d, J=8.1 Hz,1H); 8.34 (s, 1H); 8.39 (s, 1H); 9.47 (s, 1H).

EXAMPLE 170N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(4-bromo-3-methylphenyl)urea

The desired product was prepared by substituting Example 165D and4-bromo-3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 483.9, 485.9, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.33 (s, 3H); 3.93 (s, 3H); 7.01 (dd, J=8.3,1.9 Hz, 1H); 7.13 (d, J=1.7 Hz, 1H); 7.26 (dd, J=8.8, 2.7 Hz, 1H);7.45-7.48 (m, 3H); 8.27 (d, J=8.1 Hz, 1H); 8.34 (s, 1H); 8.41 (s, 1H);9.45 (s, 1H).

EXAMPLE 171N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(4-chloro-3-methoxyphenyl)urea

The desired product was prepared by substituting Example 165D and4-chloro-3-methoxyphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 456.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 3.82 (s, 3H); 3.93 (s, 3H); 7.01 (dd, J=8.3,1.9 Hz, 1H); 7.10 (d, J=9.1 Hz, 1H); 7.13 (d, J=1.7 Hz, 1H); 7.24 (dd,J=8.8, 2.7 Hz, 1H); 7.46 (s, 1H); 7.69 (d, J=2.4 Hz, 1H); 8.26 (d, J=8.5Hz, 1H); 8.34 (app s, 2H); 9.36 (s, 1H).

EXAMPLE 172N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 165D and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 406.1 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.29 (s, 3H); 3.94 (s, 3H); 6.80 (d, J=7.5 Hz, 1H); 7.01(dd, J=8.3, 1.7 Hz, 1H); 7.12 (d, J=1.7 Hz, 1H); 7.17 (t, J=7.8 Hz, 1H);7.24 (d, J=8.5 Hz, 1H); 7.32 (s, 1H); 7.46 (s, 1H); 8.29 (d, J=8.5 Hz,1H); 8.34 (s, 1H); 8.38 (s, 1H); 9.31 (s, 1H).

EXAMPLE 173N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaEXAMPLE 173A 5-(4-amino-3-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting1-(3-fluorophenyl)propan-1-one for 1-(3-chlorophenyl)propan-1-oneExamples 143A-C. MS(ESI(+)) m/e 261 (M+H)⁺.

EXAMPLE 173BN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 173A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 466.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 7.27 (dd, J=8.7, 1.5 Hz, 1H); 7.40-7.45 (m,2H); 7.51 (s, 1H); 7.53 (dd, J=10.5, 9.2 Hz, 1H); 8.33 (t, J=8.5 Hz,1H); 8.34 (s, 1H); 8.66 (dd, J=7.1, 2.4 Hz, 1H); 9.33 (d, J=1.7 Hz, 1H);9.45 (d, J=2.4 Hz, 1H).

EXAMPLE 174N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 173A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 447.9 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.26 (dd, J=8.5, 1.4 Hz, 1H); 7.34-7.37 (m, 1H); 7.41(dd, J=12.2, 2.0 Hz, 1H); 7.51 (s, 1H); 7.54-7.58 (m, 2H); 8.06 (s, 1H);8.29 (t, J=8.3 Hz, 1H); 8.34 (s, 1H); 8.81 (d, J=2.7 Hz, 1H); 9.47 (s,1H).

EXAMPLE 175N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 173A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 394.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 6.83 (d, J=7.1 Hz, 1H); 7.18 (t, J=7.6 Hz,1H); 7.23-7.27 (m, 2H); 7.32 (br. s, 1H); 7.39 (dd, J=12.0, 1.9 Hz, 1H);7.49 (s, 1H); 8.30 (d, J=8.5 Hz, 1H); 8.34 (s, 1H); 8.70 (d, J=2.7 Hz,1H); 9.06 (s, 1H).

EXAMPLE 176N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-methylphenyl)ureaEXAMPLE 176A 2-amino-4-(3-chlorophenyl)-3-thiophenecarbonitrile

The desired product was prepared by substituting1-(3-chlorophenyl)ethanone for Example 165A in Examples 165B-C. MS(ESI(+)) m/e 233 (M−H)⁻.

EXAMPLE 176B 5-(3-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 176A forExample 1C in Example 1D.

EXAMPLE 176C 5-(4-amino-3-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 176B forExample 143A in Examples 143B and 143C.

EXAMPLE 176DN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 176C and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 409.9 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 6.83 (d, J=7.1 Hz, 1H); 7.19 (app t, J=7.6Hz, 1H); 7.26 (d, J=8.1 Hz, 1H); 7.33 (s, 1H); 7.39 (dd, J=8.7, 2.2 Hz,1H); 7.52 (s, 1H); 7.58 (d, J=2.0 Hz, 1H); 8.34 (d, J=8.8 Hz, 1H); 8.34(s, 1H); 8.44 (s, 1H); 9.43 (s, 1H).

EXAMPLE 177N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 176C and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 481.9 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (dd, J=8.5, 2.0 Hz, 1H); 7.41-7.45 (m,1H); 7.50-7.57 (m, 2H); 7.61 (d, J=2.0 Hz, 1H); 8.32 (d, J=8.8 Hz, 1H);8.35 (s, 1H); 8.66 (dd, J=7.6, 2.2 Hz, 1H); 9.08 (s, 1H); 9.78 (d, J=2.0Hz, 1H).

EXAMPLE 178N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 176C and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 463.9 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.34-7.38 (m, 1H); 7.41 (dd, J=8.5, 2.0 Hz, 1H); 7.53(s, 1H); 7.55-7.59 (m, 2H); 7.61 (d, J=2.0 Hz, 1H); 8.06 (s, 1H); 8.32(d, J=8.5 Hz, 1H); 8.35 (s, 1H); 8.54 (s, 1H); 9.83 (s, 1H).

EXAMPLE 179N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylbutyl)urea

A 0° C. solution of Example 58D (150 mg, 0.62 mmol) in THF (5 mL) wastreated with triethylamine (0.09 mL) and 4-nitrophenyl chloroformate(137 mg, 0.68 mmol), stirred at 0° C. for 1 hour, treated with3-methylbutylamine (0.145 mL, 1.2 mmol) and triethylamine (0.09 mL),warmed to room temperature, and stirred overnight. The reaction mixturewas concentrated and the residue was purified by preparative HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using agradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes (10minute run time) at a flow rate of 40 mL/minute to provide 24 mg (11%yield) of the desired product. MS (ESI(+)) m/e 356.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.90 (d, J=6.4 Hz, 6H); 1.34 (q, J=6.9 Hz, 2H);1.57-1.66 (m, 1H); 3.12 (q, J=6.4 Hz, 2H); 6.16 (t, J=5.8 Hz, 1H); 7.32(d, J=8.8 Hz, 2H); 7.39 (s, 1H); 7.53 (d, J=8.8 Hz, 2H); 8.33 (s, 1H);8.60 (s, 1H).

EXAMPLE 180N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-ethylbutyl)urea

The desired product was prepared by substituting 2-ethylbutylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 370.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 0.81-0.90 (m, 6H); 1.25-1.33 (m, 5H); 3.07 (t,J=5.7 Hz, 2H); 6.19 (t, J=5.7 Hz, 1H); 7.32 (d, J=8.8 Hz, 2H); 7.39 (s,1H); 7.53 (d, J=8.8 Hz, 2H); 8.33 (s, 1H); 8.60 (s, 1H).

EXAMPLE 181N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(3-methylphenyl)ureaEXAMPLE 181A 5-(4-amino-2-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 2-fluoro-4-nitrobenzoylchloride for 3-methoxy-4-nitrobenzoyl chloride in Examples 165A-D. MS(ESI(+)) m/e 260.9 (M+H)⁺.

EXAMPLE 181BN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 181A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 394.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 2.29 (s, 3H); 6.82 (d, J=7.5 Hz, 1H); 7.18 (t, J=7.8 Hz,1H); 7.25 (d, J=10.0 Hz, 1H); 7.27 (dd, J=8.6, 2.0 Hz, 1H); 7.32 (s,1H); 7.37 (t, J=8.4 Hz, 1H); 7.52 (s, 1H); 7.66 (dd, J=12.6, 2.0 Hz,1H); 8.34 (s, 1H); 8.75 (s, 1H); 9.09 (s, 1H).

EXAMPLE 182N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 181A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 466.0 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 7.28 (dd, J=8.4, 2.2 Hz, 1H); 7.40 (t, J=8.4Hz, 1H); 7.40-7.43 (m, 1H); 7.50 (d, J=10.6 Hz, 1H); 7.52 (s, 1H); 7.66(dd, J=12.2, 1.9 Hz, 1H); 8.33 (s, 1H); 8.58 (dd, J=7.5, 2.2 Hz, 1H);9.04 (s, 1H); 9.57 (s, 1H).

EXAMPLE 183N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 181A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 448.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 7.31 (dd, J=8.4, 2.2 Hz, 1H); 7.33 (d, J=7.8 Hz, 1H);7.38 (t, J=8.4 Hz, 1H); 7.52 (s, 1H); 7.53 (t, J=8.1 Hz, 1H); 7.61 (d,J=8.4 Hz, 1H); 7.65 (dd, J=12.3, 2.0 Hz, 1H); 8.01 (s, 1H); 8.33 (s,1H); 9.20 (s, 1H); 9.22 (s, 1H).

EXAMPLE 184N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 181A and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 412.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 2.27 (s, 3H); 6.83 (ddd, J=8.4, 4.7, 1.6 Hz, 1H); 7.11(dd, J=11.4, 8.3 Hz, 1H); 7.24 (dd, J=8.5, 1.9 Hz, 1H); 7.37 (t, J=8.5Hz, 1H); 7.51 (s, 1H); 7.66 (dd, J=12.3, 2.0 Hz, 1H); 7.94 (dd, J=8.0,1.7 Hz, 1H); 8.33 (s, 1H); 8.62 (s, 1H); 9.47 (s, 1H).

EXAMPLE 185N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 181A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(−)) m/e 412.0 (M−H)⁻; ¹H NMR (500MHz, DMSO-d₆) δ 7.04 (td, J=4.4, 2.2 Hz, 1H); 7.28-7.33 (m, 3H); 7.37(t, J=8.4 Hz, 1H); 7.51 (s, 1H); 7.64 (dd, J=12.3, 2.0 Hz, 1H); 7.71 (s,1H); 8.33 (s, 1H); 9.06 (s, 1H); 9.20 (s, 1H).

EXAMPLE 186N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 181A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 408.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 2.23 (s, 6H); 6.64 (s, 1H); 7.08 (s, 2H); 7.25 (dd,J=8.4, 2.2 Hz, 1H); 7.36 (t, J=8.4 Hz, 1H); 7.50 (s, 1H); 7.65 (dd,J=12.5, 2.2 Hz, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 9.08 (s, 1H).

EXAMPLE 187N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(4-chloro-3-methylphenyl)urea

The desired product was prepared by substituting Example 181A and4-chloro-3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(−)) m/e 426.0 (M−H)⁻; ¹H NMR (500MHz, DMSO-d₆) δ 2.27 (s, 3H); 7.23 (dd, J=8.3, 2.0 Hz, 1H); 7.26 (d,J=8.4 Hz, 1H); 7.29 (dd, J=8.3, 2.0 Hz, 1H); 7.38 (t, J=8.4 Hz, 1H);7.52 (s, 1H); 7.64 (dd, J=12.2, 1.9 Hz, 1H); 7.70 (d, J=1.9 Hz, 1H);8.34 (s, 1H); 8.97 (s, 1H); 9.19 (s, 1H).

EXAMPLE 188N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 181A and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(−)) m/e 403.0 (M−H)⁻; ¹H NMR (500MHz, DMSO-d₆) δ 7.32 (dd, J=8.4, 2.2 Hz, 1H); 7.40 (t, J=8.4 Hz, 1H);7.45 (ddd, J=7.6, 1.3, 1.1 Hz, 1H); 7.52 (t, J=8.0 Hz, 1H); 7.53 (s,1H); 7.65 (dd, J=12.3, 2.0 Hz, 1H); 7.71 (ddd, J=8.1, 2.2, 0.9 Hz, 1H);7.99 (s, 1H); 8.34 (s, 1H); 9.19 (s, 1H); 9.28 (s, 1H).

EXAMPLE 189N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methylbenzyl)urea

The desired product was prepared substituting 2-methylbenzylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 390.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.31 (s, 3H); 4.30 (d, J=5.4 Hz, 2H); 6.58 (t,J=5.6 Hz, 1H); 7.17-7.19 (m, 3H); 7.25-7.29 (m, 1H); 7.33 (d, J=8.5 Hz,2H); 7.39 (s, 1H); 7.55 (d, J=8.5 Hz, 2H); 8.33 (s, 1H); 8.73 (s, 1H).

EXAMPLE 190N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-butylurea

The desired product was prepared substituting butylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 342.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 0.90 (t, J=7.1 Hz, 3H); 1.26-1.47 (m, 4H); 3.10 (q,J=6.4 Hz, 2H); 6.20 (t, J=5.3 Hz, 1H); 7.32 (d, J=8.8 Hz, 2H); 7.43 (s,1H); 7.54 (d, J=8.8 Hz, 2H); 8.36 (s, 1H); 8.61 (s, 1H).

EXAMPLE 191N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methylbutyl)urea

The desired product was prepared substituting 2-methylbutylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 356.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 0.87 (d, J=6.8 Hz, 3H); 0.88 (t, J=7.8 Hz, 3H);1.05-1.19 (m, 1H); 1.32-1.57 (m, 2H); 2.89-2.98 (m, 1H); 3.01-3.10 (m,1H); 6.23 (t, J=5.9 Hz, 1H); 7.32 (d, J=8.5 Hz, 2H); 7.39 (s, 1H); 7.53(d, J=8.5 Hz, 2H); 8.32 (s, 1H); 8.60 (s, 1H).

EXAMPLE 192N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methoxy-1-methylethyl)urea

The desired product was prepared substituting1-methyl-2-methoxyethylamine for 3-methylbutylamine in Example 179. MS(ESI(+)) m/e 358.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.10 (d, J=6.8Hz, 3H); 3.25-3.37 (m, 2H); 3.30 (s, 3H); 3.82-3.90 (m, 1H); 6.16 (d,J=8.1 Hz, 1H); 7.32 (d, J=8.5 Hz, 2H); 7.40 (s, 1H); 7.52 (d, J=8.5 Hz,2H); 8.34 (s, 1H); 8.65 (s, 1H).

EXAMPLE 193N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylbenzyl)urea

The desired product was prepared substituting 3-methylbenzylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 390.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.30 (s, 3H); 4.28 (d, J=5.8 Hz, 2H); 6.67 (t,J=6.1 Hz, 1H); 7.05-7.13 (m, 3H); 7.23 (t, J=7.3 Hz, 1H); 7.34 (d, J=8.8Hz, 2H); 7.42 (s, 1H); 7.56 (d, J=8.8 Hz, 2H); 8.35 (s, 1H); 8.77 (s,1H).

EXAMPLE 194N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(dimethylamino)phenyl]urea

The desired product was prepared as the TFA salt by substituting4-N,N-dimethyl aniline for 3-methylbutylamine in Example 179. MS(ESI(+)) m/e 405.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.84 (s, 6H);6.71 (d, J=9.2 Hz, 2H); 7.27 (d, J=9.2 Hz, 2H); 7.37 (d, J=8.8 Hz, 2H);7.42 (s, 1H); 7.59 (d, J=8.8 Hz, 2H); 8.33 (s, 1H); 8.37 (s, 1H); 8.74(s, 1H).

EXAMPLE 195N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-hydroxyphenyl)urea

The desired product was prepared as the TFA salt by substituting3-hydroxyaniline for 3-methylbutylamine in Example 179. MS (ESI(+)) m/e378.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.39 (dd, J=8.1, 2.4 Hz, 1H);6.81 (dd, J=7.6, 1.5 Hz, 1H); 7.00-7.08 (m, 2H); 7.39 (d, J=8.5 Hz, 2H);7.47 (s, 1H); 7.60 (d, J=8.5 Hz, 2H); 8.38 (s, 1H); 8.65 (s, 1H); 8.83(s, 1H); 9.34 (s, 1H).

EXAMPLE 196N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-isobutylurea

The desired product was prepared substituting 2-methylpropylamine for3-methylbutylamine in Example 179. MS (ESI(+)) m/e 342.0 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 0.88 (d, J=6.4 Hz, 6H); 1.66-1.75 (m, 1H); 2.94(app t, J=6.3 Hz, 2H); 6.26 (t, J=5.9 Hz, 1H); 7.33 (d, J=8.5 Hz, 2H);7.44 (s, 1H); 7.54 (d, J=8.5 Hz, 2H); 8.38 (s, 1H); 8.62 (s, 1H).

EXAMPLE 197N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-N′-[3-(trifluoromethyl)phenyl]ureaEXAMPLE 197A 2-amino-4-(2-chloro-4-nitrophenyl)-3-thiophenecarbonitrile

The desired product was prepared substituting 2-chloro-4-nitrobenzoylchloride for 3-methoxy-4-nitrobenzoyl chloride in Examples 165A-C. MS(ESI(+)) m/e 277.9 (M+H)⁺.

EXAMPLE 197B 5-(2-chloro-4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amine

A suspension of Example 197A (3.95 g, 141.1 mmol) intriethylorthoformate (50 mL) was treated with ammonium sulfate (186 mg,1.4 mmol), heated to reflux for 4 hours, cooled to room temperature,treated with 2M ammonia in ethanol (100 mL), stirred for 2 hours, andfiltered. The filter cake (2.6 g) was suspended in o-dichlorobenzene (30mL) and heated to reflux until all the material dissolved (about 2hours). The solution of was cooled to room temperature and filtered. Thefilter cake was dried to provide 2.14 g of the desired product. MS(ESI(+)) m/e 306.9, 308.9 (M+H)⁺.

EXAMPLE 197C 5-(4-amino-2-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 197B forExample 1D in Example 1E. MS (ESI(+)) m/e 277, 279 (M+H)⁺.

EXAMPLE 197DN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 197C and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 463.9, 465.9 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 7.35 (d, J=7.5 Hz, 1H); 7.43 (d, J=8.1 Hz, 1H);7.47 (dd, J=8.5, 2.0 Hz, 1H); 7.49 (s, 1H); 7.54 (t, J=8.1 Hz, 1H); 7.62(d, J=8.5 Hz, 1H); 7.91 (d, J=1.7 Hz, 1H); 8.03 (br. s, 1H); 8.34 (s,1H); 9.20 (s, 1H); 9.22 (s, 1H).

EXAMPLE 198N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 197C and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 429.9, 431.9 (M+H)⁺, ¹H NMR(300 MHz, DMSO-d₆) δ 7.04-7.07 (m, 1H); 7.31-7.33 (m, 2H); 7.42-7.44 (m,2H); 7.49 (s, 1H); 7.72 (dd, J=2.7, 1.7 Hz, 1H); 7.90 (d, J=1.0 Hz, 1H);8.33 (s, 1H); 9.05 (s, 1H); 9.16 (s, 1H).

EXAMPLE 199N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 197C and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 481.9, 483.9(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.47 (m, 3H); 7.50 (s, 1H);7.51-7.58 (m, 1H); 7.92 (d, J=1.4 Hz, 1H); 8.34 (s, 1H); 8.59 (dd,J=7.5, 2.0 Hz, 1H); 9.03 (d, J=2.7 Hz, 1H); 9.52 (s, 1H).

EXAMPLE 200N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 197C and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 409.9, 411.9 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 6.82 (d, J=7.5 Hz, 1H); 7.18 (t,J=7.5 Hz, 1H); 7.23-7.26 (m, 1H); 7.31-7.34 (br. s, 1H); 7.41-7.42 (m,2H); 7.49 (s, 1H); 7.91 (br. s, 1H); 8.33 (s, 1H); 8.75 (s, 1H); 9.05(s, 1H).

EXAMPLE 201N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-methoxyphenyl]-N′-(3-methylphenyl)ureaEXAMPLE 201A 5-(4-amino-2-methoxyphenyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting2-methoxy-4-nitrobenzoyl chloride for 3-methoxy-4-nitrobenzoyl chloridein Examples 165A-D. MS (ESI(+)) m/e 273 (M+H)⁺.

EXAMPLE 201BN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-methoxyphenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 201A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 406.0 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s,3H); 3.72 (s, 3H); 6.81 (d, J=7.1 Hz, 1H); 7.05 (dd, J=8.1, 2.0 Hz, 1H);7.14-7.25 (m, 3H); 7.34 (s, 1H); 7.38 (s, 1H); 7.50 (d, J=2.0 Hz, 1H);8.36 (s, 1H); 8.67 (s, 1H); 8.93 (s, 1H).

EXAMPLE 202N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-methoxyphenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 201A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 460.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.72 (s, 3H); 7.08 (dd, J=8.3, 1.9 Hz, 1H); 7.23 (d,J=8.1 Hz, 1H); 7.32-7.35 (m, 2H); 7.49 (d, J=2.0 Hz, 1H); 7.53 (t, J=8.0Hz, 1H); 7.60 (d, J=8.5 Hz, 1H); 8.04 (s, 1H); 8.32 (s, 1H); 9.05 (s,1H); 9.12 (s, 1H).

EXAMPLE 203N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-methoxyphenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 201A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 425.9 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.72 (s, 3H); 7.04 (dt, J=6.7, 2.0 Hz, 1H); 7.07 (dd,J=8.1, 2.0 Hz, 1H); 7.23 (d, J=8.1 Hz, 1H); 7.27-7.35 (m, 2H); 7.39 (s,1H); 7.49 (d, J=1.7 Hz, 1H); 7.75 (t, J=2.0 Hz, 1H); 8.36 (s, 1H); 9.00(s, 1H); 9.06 (s, 1H).

EXAMPLE 204N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-methoxyphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 201A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 478.0 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 3.74 (s, 3H); 7.06 (dd, J=8.1, 2.0 Hz, 1H);7.24 (d, J=8.1 Hz, 1H); 7.35 (s, 1H); 7.42 (ddd, J=8.5, 4.4, 2.4 Hz,1H); 7.47 (d, J=2.0 Hz, 1H); 7.52 (dd, J=10.5, 8.8 Hz, 1H); 8.31 (s,1H); 8.62 (dd, J=7.3, 2.2 Hz, 1H); 8.96 (d, J=3.0 Hz, 1H); 9.43 (s, 1H).

EXAMPLE 205N-[5-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-pyridinyl]-N′-(3-methylphenyl)ureaEXAMPLE 205A 5-(6-chloro-3-pyridinyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 6-chloronicotinoylchloride for 3-methoxy-4-nitrobenzoyl chloride in Examples 197A-B. MS(ESI(+)) m/e 263 (M+H)⁺.

EXAMPLE 205B 5-(6-amino-3-pyridinyl)thieno[2,3-d]pyrimidin-4-amine

A solution of Example 205A (1.64 g, 6.25 mmol) in dioxane (75 mL) andNH₄OH (75 mL) was heated to 175° C. in a sealed tube for 2.5 days. Thecrude solution was filtered and the filtrate was concentrated under astream of nitrogen. The residue was purified by silica gelchromatography with 3 to 5% methanol/dichloromethane to provide 0.69 g(45% yield) of Example 205B as a yellow solid. MS (ESI(+)) m/e 244(M+H)⁺.

EXAMPLE 205CN-[5-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-pyridinyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 205B and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 377.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.30 (s, 3H); 6.85 (d, J=7.5 Hz, 1H); 7.20 (t, J=7.5 Hz,1H); 7.35 (d, J=8.1 Hz, 1H); 7.37 (s, 1H); 7.54 (s, 1H); 7.62 (d, J=8.5Hz, 1H); 7.83 (dd, J=8.5, 2.4 Hz, 1H); 8.35 (s, 1H); 8.39 (d, J=2.4 Hz,1H); 9.60 (s, 1H); 10.42 (s, 1H).

EXAMPLE 206N-{4-[4-amino-6-(3-hydroxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substitutingtert-butyl(4-iodobutoxy)dimethylsilane) fortert-butyl(3-iodopropoxy)dimethylsilane) in Examples 104A-D. MS (ESI(+))m/e 434 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.70 (m, 2H); 2.29 (s, 3H);2.68 (m, J=6.27 Hz, 2H); 3.37 (t, J=6.27 Hz, 2H); 6.81 (d, J=7.80 Hz,1H); 7.17 (t, J=7.63 Hz, 1H); 7.23-7.33 (m, 4H); 7.62 (d, J=8.81 Hz,2H); 8.27 (s, 1H); 8.69 (s, 1H); 8.90 (s, 1H).

EXAMPLE 207N-{4-[4-amino-6-(3-hydroxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substitutingtert-butyl(4-iodobutoxy)dimethylsilane) and 3-trifluoromethylphenylisocyanate for tert-butyl(3-iodopropoxy)dimethylsilane) and3-methylphenyl isocyanate, respectively, in Examples 104A-D. MS (ESI(+))m/e 488 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.70 (m, 2H); 2.68 (t, J=7.5Hz, 2H); 3.37 (q, J=6.0 Hz, 2H); 4.48 (t, J=5.09 Hz, 1H); 7.32 (m, 3H);7.29-7.35 (t, J=7.97 Hz, 1H); 7.58-7.67 (m, 3H); 8.03 (s, 1H); 8.27 (s,1H); 9.03 (s, 1H); 9.15 (s, 1H).

EXAMPLE 208N-{4-[4-amino-6-(3-hydroxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substitutingtert-butyl(4-iodobutoxy)dimethylsilane) and 3-chloromethylphenylisocyanate for tert-butyl(3-iodopropoxy)dimethylsilane) and3-methylphenyl isocyanate respectively, in Examples 104A-D. MS (ESI(+))m/e 454 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.71 (m, 2H); 2.68 (t, J=6.0Hz, 2H); 3.37 (m, 1H); 4.48 (t, J=6.0 Hz, 1H); 7.04 (m, 1H); 7.31 (m,4H); 7.63 (d, J=8.48 Hz, 2H); 7.73 (t, J=1.86 Hz, 1H); 8.26 (s, 1H);8.98 (s, 2H).

EXAMPLE 209N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 58D and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 380 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 6.80 (m, 1H); 7.14 (m, J=7.29, 1H); 7.32 (m, 1H); 7.40(m, 3H); 7.51 (m, 1H); 7.60 (m, 2H); 8.34 (s, 1H); 8.96 (s, 1H); 8.99(s, 1H).

EXAMPLE 210N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 58D and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 3878 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.38-7.47 (m, 3H); 7.51 (t, J=7.80 Hz, 2H); 7.62 (d,J=8.82 Hz, 2H); 7.71 (m, 1H); 7.99 (s, 1H); 8.34 (s, 1H); 9.06 (s, 1H);9.10 (s, 1H).

EXAMPLE 211 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 58D and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 6.63 (s, 1H); 7.09 (s, 2H); 7.39 (d, J=8.48 Hz, 2H);7.43 (s, 1H); 7.60 (d, J=8.82 Hz, 2H); 8.34 (s, 1H); 8.58 (s, 1H); 8.84(s, 1H).

EXAMPLE 212N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 58D and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 440, 442 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 7.17 (d, J=7.80 Hz, 1H); 7.25 (t, J=7.80 Hz, 1H);7.34 (m, 1H); 7.40 (d, J=8.48 Hz, 2H); 7.44 (s, 1H); 7.61 (d, J=8.82 Hz,2H); 7.87 (t, J=1.87 Hz, 1H); 8.34 (s, 1H); 8.95 (s, 1H); 8.97 (s, 1H).

EXAMPLE 213 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,4-dimethylphenyl)urea

The desired product was prepared by substituting Example 58D and3,4-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.16 (s, 3H); 2.20 (s, 3H); 7.03 (d, J=8.14 Hz, 1H);7.18 (m, 1H); 7.24 (s, 1H); 7.38 (d, J=8.81 Hz, 2H); 7.43 (s, 1H); 7.60(d, J=8.48 Hz, 2H); 8.34 (s, 1H); 8.55 (s, 1H); 8.82 (s, 1H).

EXAMPLE 214N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-2,3-dihydro-1H-inden-5-ylurea

The desired product was prepared by substituting Example 58D and5-isocyanatoindane for Example 1E and phenyl isocyanate, respectively,in Example 1F. MS (ESI(+)) m/e 402 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.00 (m, 2H); 2.82 (m, 4H); 7.14 (m, 2H); 7.38 (d, J=8.82 Hz, 2H); 7.40(s, 1H); 7.43 (s, 1H); 7.60 (d, J=8.48 Hz, 2H); 8.34 (s, 1H); 8.60 (s,1H); 8.83 (s, 1H).

EXAMPLE 215N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-bromo-3-methylphenyl)urea

The desired product was prepared by substituting Example 58D and4-bromo-3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 454, 456 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.32 (s, 3H); 7.28 (m, 1H); 7.39 (d, J=8.82 Hz,2H); 7.43 (s, 1H); 7.47 (m, 2H); 7.61 (d, J=8.48 Hz, 2H); 8.34 (s, 1H);8.81 (s, 1H); 8.92 (s, 1H).

EXAMPLE 216N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting Example 58D and4-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 380 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.13 (t, J=8.81 Hz, 2H); 7.39 (d, J=8.81 Hz, 2H); 7.43(s, 1H); 7.48 (m, J=9.15, 5.09 Hz, 2H); 7.60 (d, J=8.81 Hz, 2H); 8.34(s, 1H); 8.78 (s, 1H); 8.88 (s, 1H).

EXAMPLE 217N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting Example 61B and4-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 458, 460 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 7.14 (t, J=8.82 Hz, 2H); 7.36 (d, J=8.48 Hz, 2H);7.49 (dd, J=8.99, 4.92 Hz, 2H); 7.65 (d, J=8.48 Hz, 2H); 8.33 (s, 1H);8.81 (s, 1H); 8.94 (s, 1H).

EXAMPLE 218N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 61B and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 458, 460 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 6.81 (m, 1H); 7.15 (d, J=7.80 Hz, 1H); 7.34 (m,3H); 7.51 (d, J=11.87 Hz, 1H); 7.66 (d, J=8.48 Hz, 2H); 8.33 (s, 1H);9.02 (s, 2H).

EXAMPLE 219N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 61B and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 465, 467 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 7.38 (d, J=8.48 Hz, 2H); 7.45 (d, J=7.80 Hz, 1H);7.52 (t, J=7.80 Hz, 1H); 7.67 (d, J=8.48 Hz, 2H); 7.71 (d, J=8.82 Hz,1H); 8.00 (s, 1H); 8.33 (s, 1H); 9.12 (s, 1H); 9.14 (s, 1H).

EXAMPLE 220N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 61B and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 468, 470 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.24 (s, 6H); 6.64 (s, 1H); 7.09 (s, 2H); 7.35 (d,J=8.48 Hz, 2H); 7.65 (d, J=8.82 Hz, 2H); 8.33 (s, 1H); 8.61 (s, 1H);8.90 (s, 1H).

EXAMPLE 221N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N-(3-bromophenyl)urea

The desired product was prepared by substituting Example 61B and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 520 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.17 (d, J=7.80 Hz, 1H); 7.26 (t, J=7.97 Hz, 1H); 7.34(d, J=7.80 Hz, 1H); 7.37 (d, J=8.48 Hz, 2H); 7.66 (d, J=8.48 Hz, 2H);7.88 (s, 1H); 8.33 (s, 1H); 8.99 (s, 1H); 9.03 (s, 1H).

EXAMPLE 222N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,4-dimethylphenyl)urea

The desired product was prepared by substituting Example 61B and3,4-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 466, 468 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.16 (s, 3H); 2.20 (s, 3H); 7.04 (d, J=8.48 Hz,1H); 7.19 (d, J=10.17 Hz, 1H); 7.25 (s, 1H); 7.34 (d, J=8.48 Hz, 2H);7.64 (d, J=8.48 Hz, 2H); 8.32 (s, 1H); 8.58 (s, 1H); 8.88 (s, 1H).

EXAMPLE 223N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 61B and3-fluoro-4-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 526, 528(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37 (d, J=8.82 Hz, 2H); 7.46 (t,J=9.83 Hz, 1H); 7.66 (m, 3H); 8.03 (dd, J=6.44, 2.71 Hz, 1H); 8.33 (s,1H); 9.08 (s, 1H); 9.15 (s, 1H).

EXAMPLE 224N-[4-(4-amino-6-bromothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-bromo-3-methylphenyl)urea

The desired product was prepared by substituting Example 61B and4-bromo-3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 534 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.32 (d, J=5.09 Hz, 3H); 7.28 (dd, J=8.48, 2.71 Hz, 1H);7.36 (d, J=8.48 Hz, 2H); 7.47 (m, 2H); 7.65 (d, J=8.48 Hz, 2H); 8.33 (s,1H); 8.85 (s, 1H); 8.98 (s, 1H).

EXAMPLE 225N-{4-[4-amino-6-(4-pyridinylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 14B and3-cyanophenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS (ESI(+)) m/e 478 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.28-7.33 (m, 1H); 7.37-7.40 (d, 2H, J=8.4Hz); 7.42-7.46 (td, 1H, J=1.2, 9 Hz); 7.49-7.56 (m, 2H); 7.65-7.67 (d,2H, J=8.7 Hz); 7.68-7.72 (m, 1H); 7.99-7.80 (t, 1H, J=1.8 Hz); 8.27 (s,1H); 8.33-8.34 (d, 1H, J=1.5 Hz); 8.41-8.44 (dd, 1H, J=1.5, 4.8 Hz);9.09 (s, 1H); 9.12 (s, 1H).

EXAMPLE 226N-{4-[4-amino-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 115A and3-bromophenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS (ESI(+)) m/e 531, 533 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 4.04 (s, 2H); 7.15-7.35 (m, 4H); 7.36-7.39 (d, 2H,J=8.7 Hz); 7.52-7.56 (td, 1H, J=2.4, 7.5 Hz); 7.64-7.67 (d, 2H, J=9 Hz);7.87-7.88 (t, 1H, J=2.1 Hz); 8.27 (s, 1H); 8.34-8.35 (d, 1H, J=1.5 Hz);8.41-8.44 (dd, 1H, J=1.8, 4.8 Hz); 8.97 (s, 1H); 8.99 (s, 1H).

EXAMPLE 227N-{4-[4-amino-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 115A and3-ethylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 481 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16-1.21 (t, 3H, J=7.5 Hz); 2.55-2.62 (q, 2H, J=7.5Hz); 4.04 (s, 2H); 6.83-6.86 (d, 1H, J=7.5 Hz); 7.17-7.22 (t, 1H, J=7.5Hz); 7.26-7.38 (m, 5H); 7.53-7.56 (td, 1H, J=1.5, 8.1 Hz); 7.63-7.66 (d,2H, J=9 Hz); 8.27 (s, 1H); 8.34-8.35 (d, 1H, J=1.5 Hz); 8.42-8.44 (dd,1H, J=1.8, 4.8 Hz); 8.70 (s, 1H); 8.9 (s, 1H).

EXAMPLE 228N-{4-[4-amino-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 115A and5-methyl-2-fluorophenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 485 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.28 (s, 3H); 4.04 (s, 2H); 6.79-6.85 (m 1H); 7.08-7.15(dd, 1H, J=8.4, 11.7 Hz); 7.30-7.34 (dd, 1H, J=4.5, 7.2 Hz); 7.36-7.39(d, 2H, J=8.4 Hz); 7.53-7.57 (td, 1H, J=1.8, 7.8 Hz); 7.63-7.66 (d, 2H,J=8.7 Hz); 7.97-8.01 (dd, 1H, J=2.1, 7.8 Hz); 8.27 (s, 1H); 8.34-8.35(d, 1H, J=1.8 Hz); 8.42-8.44 (dd, 1H, J=1.5, 4.8 Hz); 8.56-8.57 (d, 1H,J=2.4 Hz); 9.30 (s, 1H).

EXAMPLE 229N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaEXAMPLE 229AN-{4-[4-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 104B and5-trifluoromethyl-2-fluorophenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F.

EXAMPLE 229BN-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 229A forExample 104C in Example 104D. MS (ESI(+)) m/e 492 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.74-2.79 (t, 2H, J=6.6 Hz); 3.54-3.60 (q, 2H, J=6.6Hz); 4.87-4.91 (t, 1H, J=5.4 Hz); 7.33-7.36 (d, 2H, J=8.7 Hz); 7.38-7.44(m, 1H); 7.49-7.55 (m, 1H); 7.63-7.66 (d, 2H, J=8.4 Hz); 8.27 (s, 1H);8.62-8.65 (dd, 1H, J=1.8, 6.9 Hz); 8.98-8.99 (d, 1H, J=3.7 Hz); 9.39 (s,1H).

EXAMPLE 230N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-ethylphenyl)ureaEXAMPLE 230AN-{4-[4-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 104B and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F.

EXAMPLE 230BN-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 230A forExample 104C in Example 104D. MS (ESI(+)) m/e 434 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16-1.21 (t, 3H, J=7.8 Hz); 2.55-2.62 (q, 2H, J=7.8Hz); 2.75-2.79 (t, 2H, J=6.3 Hz); 3.54-3.58 (q, 2H, J=5.4 Hz); 4.85-4.89(t, 1H, J=5.7 Hz); 6.83-6.85 (d, 1H, J=7.2 Hz); 7.17-7.22 (t, 1H, J=7.5Hz); 7.26-7.34 (m, 4H,), 7.61-7.64 (d, 2H, J=8.4 Hz); 8.26 (s, 1H); 8.68(s, 1H); 8.86 (s, 1H).

EXAMPLE 231N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-cyanophenyl)ureaEXAMPLE 231AN-{4-[4-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 104B and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F.

EXAMPLE 231BN-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 231A forExample 104C in Example 104D. MS (ESI(+)) m/e 431 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.75-2.79 (t, 2H, J=6.9 Hz); 3.54-3.60 (q, 2H, J=5.1Hz); 4.86-4.89 (t, 1H, J=5.1 Hz); 7.32-7.35 (d, 2H, J=8.7 Hz); 7.42-7.46(td, 1H, J=1.2, 7.5 Hz); 7.49-7.54 (t, 1H, J=7.8 Hz); 7.62-7.65 (d, 2H,J=8.4 Hz); 7.69-7.73 (td, 1H, J=1.2, 8.1 Hz); 7.99-8.00 (t, 1H, J=1.8Hz); 8.27 (s, 1H); 9.07 (s, 1H); 9.12 (s, 1H).

EXAMPLE 232N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-bromophenyl)ureaEXAMPLE 232AN-{4-[4-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 104B and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F.

EXAMPLE 232BN-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 232A forExample 104C in Example 104D. MS (ESI(+)) m/e 484, 486 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.74-2.79 (t, 2H, J=6.3 Hz); 3.54-3.59 (t, 2H,J=6.0 Hz); 4.81-4.90 (br, 1H); 7.15-7.18 (m, 1H); 7.23-7.28 (t, 1H,J=7.8 Hz); 7.31-7.36 (m, 3H); 7.61-7.64 (d, 2H, J=8.7 Hz); 7.87-7.88 (t,1H, J=1.8 Hz); 8.27 (s, 1H); 8.96 (s, 1H); 8.98 (s, 1H).

EXAMPLE 233N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 108 and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 445 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.83-2.87 (t, 2H, J=6.3 Hz); 3.22 (s, 3H); 3.47-3.52 (t,2H, J=6.3 Hz); 7.32-7.35 (d, 2H, J=8.7 Hz); 7.43-7.46 (td, 1H, J=1.2,7.8 Hz); 7.49-7.54 (t, 1H, J=7.8 Hz); 7.63-7.66 (d, 2H, J=8.7 Hz);7.68-7.73 (m, 1H); 7.99-8.00 (t, 1H, J=1.8 Hz); 8.27 (s, 1H); 9.08 (s,1H); 9.12 (s, 1H).

EXAMPLE 234N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 108 and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 448 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16-1.21 (t, 3H, J=7.5 Hz); 2.55-2.62 (q, 2H, J=7.5Hz); 2.83-2.87 (t, 2H, J=6.0 Hz); 3.22 (s, 3H); 3.48-3.52 (t, 2H, J=6.6Hz); 6.83-6.86 (d, 1H, J=7.5 Hz); 7.17-7.22 (t, 1H, J=7.5 Hz); 7.26-7.34(m, 4H); 7.61-7.64 (d, 2H, J=8.4 Hz); 8.27 (s, 1H); 8.70 (s, 1H); 8.75(s, 1H).

EXAMPLE 235N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 108 and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 498, 500 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.83-2.87 (t, 2H, J=6 Hz); 3.22 (s, 3H); 3.47-3.52(t, 2H, J=6.3 Hz); 7.15-7.19 (td, 1H, J=1.5, 8.1 Hz); 7.23-7.28 (t, 1H,J=7.8 Hz); 7.31-7.36 (m, 3H); 7.62-7.65 (d, 2H, J=9 Hz); 7.87-7.88 (t,1H, J=1.8 Hz); 8.27(s, 1H); 8.97 (s, 1H); 8.98 (s, 1H).

EXAMPLE 236N-{4-[4-amino-6-(2-methoxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 108 and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 454, 456 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.83-2.87 (t, 2H, J=6.3 Hz); 3.22 (s, 3H);3.48-3.52 (t, 2H, J=6.6 Hz); 7.02-7.06 (td, 1H, J=2.1, 6.6 Hz);7.30-7.34 (m, 4H); 7.62-7.65 (d,2H, J=8.7 Hz); 7.72-7.75 (br, 1H);8.27(s, 1H); 8.99 (s, 2H).

EXAMPLE 237N-{4-[4-amino-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 115A and3,5-dimethylphenyl isocyanate for Example 1A and phenyl isocyanate,respectively, in Examples 1B-1F. MS(ESI(+)) m/e 481 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.24 (s, 6H); 4.04 (s, 2H); 6.63 (s, 1H); 7.09 (s, 2H);7.29-7.37 (m, 3H); 7.52-7.56 (td, 1H, J=1.8, 7.8 Hz); 7.62-7.65 (d, 2H,J=8.7 Hz); 8.27 (s, 1H); 8.34-8.35 (d, 1H, J=1.5 Hz); 8.41-8.44 (dd, 1H,J=1.8, 4.8 Hz); 8.59 (s, 1H); 8.88 (s, 1H).

EXAMPLE 2383-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)propanamideEXAMPLE 238A3-[4-amino-5-(4-aminophenyl)thieno[2,3-d]pyrimidin-6-yl]propanamide

The desired product was prepared by substituting5-oxo-5-phenyl-pentanoic acid for 1-(3-chlorophenyl)propan-1-one inExamples 143A-C. MS (ESI(+)) m/e 314 (M+H)⁺.

EXAMPLE 238B3-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)propanamide

The desired product was prepared by substituting Example 238A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 519 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.36 (t, J=7.63 Hz, 2H); 2.84 (t, J=7.46 Hz,2H); 6.84 (s, 1H); 7.34 (s, 1H); 7.35 (d, J=8.48 Hz, 2H); 7.42 (m,J=4.41, 2.71 Hz, 1H); 7.52 (m, 1H); 7.65 (d, J=8.81 Hz, 2H); 8.27 (s,1H); 8.64 (dd, J=6.95, 2.20 Hz, 1H); 8.99 (d, J=2.71 Hz, 1H); 9.41 (s,1H).

EXAMPLE 2393-{4-amino-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 447 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s,3H); 2.36 (t, J=7.63 Hz, 2H); 2.85 (t, J=7.46 Hz, 2H); 6.81 (d, J=7.46Hz, 1H); 6.85 (m, 1H); 7.17 (t, J=7.80 Hz, 1H); 7.26 (d, J=9.00 Hz, 1H);7.32 (m, 4H); 7.64 (d, J=8.81 Hz, 2H); 8.33 (s, 1H); 8.71 (s, 1H); 8.93(s, 1H).

EXAMPLE 2403-(4-amino-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)propanamide

The desired product was prepared by substituting Example 238A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 501 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (t,J=7.46 Hz, 2H); 2.84 (t, J=7.63 Hz, 2H); 6.85 (s, 1H); 7.34 (m, 4H);7.53 (t, J=7.80 Hz, 1H); 7.61 (d, J=10.17 Hz, 1H); 7.65 (d, J=8.48 Hz,2H); 8.04 (s, 1H); 8.29 (s, 1H); 9.05 (s, 1H); 9.17 (s, 1H).

EXAMPLE 2413-{4-amino-5-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluroacetate salt.MS (ESI(+)) m/e 465 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H);2.36 (t, J=7.46 Hz, 2H); 2.85 (t, J=7.29 Hz, 2H); 6.82 (m, 2H); 7.12(dd, J=11.36, 8.31 Hz, 1H); 7.33 (m, 3H); 7.64 (d, J=8.48 Hz, 2H); 7.99(dd, J=7.80, 2.03 Hz, 1H); 8.33 (s, 1H); 8.57 (d, J=2.37 Hz, 1H); 9.31(s, 1H).

EXAMPLE 2423-{4-amino-5-[4-({[(3,5-dimethylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s,6H); 2.36 (t, J=7.46 Hz, 2H); 2.85 (t, J=7.46 Hz, 2H); 6.63 (s, 1H);6.85 (s, 1H); 7.09 (s, 2H); 7.29-7.35 (m, 3H); 7.63 (d, J=8.48 Hz, 2H);8.33 (s, 1H); 8.63 (s, 1H); 8.91 (s, 1H).

EXAMPLE 2433-{4-amino-5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 467 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (t,J=7.63 Hz, 2H); 2.85 (t, J=7.63 Hz, 2H); 6.85 (s, 1H); 7.04 (m, 1H);7.29-7.37 (m, 5H); 7.64 (d, J=8.81 Hz, 2H); 7.74 (m, 1H); 8.33 (s, 1H);9.03 (s, 1H); 9.04 (s, 1H).

EXAMPLE 2443-{4-amino-5-[4-({[(3-bromophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 511, 513 (M+H); ¹H NMR (300 MHz, DMSO-d₆) δ 2.36(t, J=7.63 Hz, 2H); 2.85 (t, J=7.63 Hz, 2H); 6.85 (s, 1H); 7.17 (m, 1H);7.26 (t, J=7.97 Hz, 1H); 7.31-7.37 (m, 4H); 7.64 (d, J=8.81 Hz, 2H);7.88 (t, J=2.03 Hz, 1H); 8.32 (s, 1H); 9.00 (s, 1H); 9.03 (s, 1H).

EXAMPLE 2453-{4-amino-5-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 451 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.81 (m,1H); 6.85 (s, 1H); 7.15 (m, 1H); 7.28-7.37 (m, 4H); 7.52 (m, 1H); 7.52(dt, J=11.70, 2.30 Hz, 1H); 7.64 (d, J=8.48 Hz, 2H); 8.33 (s, 1H); 9.03(s, 1H); 9.04 (s, 1H).

EXAMPLE 2463-{4-amino-5-[4-({[(3-ethylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}propanamide

The desired product was prepared by substituting Example 238A and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t,J=7.63 Hz, 3H); 2.36 (t, J=7.46 Hz, 2H); 2.59 (q, J=7.46 Hz, 2H); 2.85(t, J=7.46 Hz, 2H); 6.84-6.87(m, 2H); 7.19 (t, J=7.80 Hz, 1H); 7.28 (d,J=9.49 Hz, 1H); 7.30-7.37 (m, J=8.81 Hz, 4H); 7.62 (s, 1H); 7.65 (s,1H); 8.33 (s, 1H); 8.72 (s, 1H); 8.92 (s, 1H).

EXAMPLE 2473-(4-amino-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamideEXAMPLE 247A 6,6-dicyano-N,N-dimethyl-5-phenyl-5-hexenamide

The desired product was prepared by substituting6,6-dicyano-5-phenyl-5-hexenoic acid (prepared by substituting5-oxo-5-phenylpentanoic acid for Example 1A in Example 1B) anddimethylamine hydrochloride for Example 66B and aniline, respectively,in Example 66C. MS (ESI(−)) m/e 266 (M−H)⁻.

EXAMPLE 247B3-(4-amino-5-phenylthieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247A forExample 1B in Examples 1C-D

EXAMPLE 247C3-[4-amino-5-(4-aminophenyl)thieno[2,3-d]pyrimidin-6-yl]-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247B forExample 143A in Examples 143B-C. MS (ESI(+)) m/e 342 (M+H)⁺.

EXAMPLE 247D3-(4-amino-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 529 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.29 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.12 Hz, 2H); 2.89 (s, 3H);7.33 (d, J=8.14 Hz, 1H); 7.36 (d, J=8.81 Hz, 2H); 7.53 (t, J=6.95 Hz,1H); 7.61 (d, J=9.83 Hz, 1H); 7.66 (d, J=8.81 Hz, 2H); 8.04 (s, 1H);8.33 (s, 1H); 9.09 (s, 1H); 9.20 (s, 1H).

EXAMPLE 2483-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. The product was purified byHPLC using the conditions described in Example 179 to provide thetrifluoroacetate salt. MS (ESI(+)) m/e 493 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.28 (s, 3H); 2.60 (t, J=7.29 Hz, 2H); 2.80 (s, 3H); 2.85 (t,J=7.12 Hz, 2H); 2.89 (s, 3H); 6.83 (m, 1H); 7.12 (dd, J=11.36, 8.31 Hz,1H); 7.35 (d, J=8.82 Hz, 2H); 7.64 (d, J=8.82 Hz, 2H); 7.99 (dd, J=7.80,2.03 Hz, 1H); 8.34 (s, 1H); 8.57 (d, J=2.71 Hz, 1H); 9.30 (s, 1H).

EXAMPLE 2493-{4-amino-5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 495 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.29 Hz, 2H); 2.80 (s, 3H); 2.85 (t, J=7.12 Hz, 2H); 2.89 (s, 3H);7.04 (m, 1H); 7.29-733 (m, 2H); 7.35 (d, J=8.82 Hz, 2H); 7.65 (d, J=8.81Hz, 2H); 7.73 (m, 1H); 8.34 (s, 1H); 9.05 (s, 1H); 9.06 (s, 1H).

EXAMPLE 2503-(4-amino-5-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-trifluoromethyl-4-chlorophenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. The product was purified byHPLC using the conditions described in Example 179 to provide thetrifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (t, J=7.29 Hz,2H); 2.80 (s, 3H); 2.84 (d, J=7.46 Hz, 2H); 2.89 (s, 3H); 7.36 (d,J=8.48 Hz, 2H); 7.60-7.68 (m, 4H); 8.14 (d, J=2.37 Hz, 1H); 8.33 (s,1H); 9.13 (s, 1H); 9.31 (s, 1H).

EXAMPLE 2513-{4-amino-5-[4-({[(4-fluorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and4-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 479 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.29 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H);7.13 (m, 2H); 7.34 (d, J=8.48 Hz, 2H); 7.49 (m, 2H); 7.64 (d, J=8.48 Hz,2H); 8.35 (s, 1H); 8.85 (s, 1H); 8.96 (s, 1H).

EXAMPLE 2523-{4-amino-5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 475 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s,3H); 2.60 (t, J=7.12 Hz, 2H); 2.80 (s, 3H); 2.87 (t, J=7.12 Hz, 2H);2.89 (s, 3H); 6.81 (d, J=7.12 Hz, 1H); 7.17 (m, 1H); 7.26 (d, J=6.0 Hz,1H); 7.32 (s, 1H); 7.34 (d, J=8.48 Hz, 2H); 7.64 (d, J=8.48 Hz, 2H);8.36 (s, 1H); 8.73 (s, 1H); 8.94 (s, 1H).

EXAMPLE 2533-{4-amino-5-[4-({[(3-bromophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 as the trifluoroacetate salt. MS(ESI(+)) m/e 561 (M+Na)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t, J=7.29Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H); 7.14-7.19(m, 1H); 7.26 (t, J=7.97 Hz, 1H); 7.32-7.38 (m, 3H); 7.65 (d, J=8.81 Hz,2H); 7.88 (t, J=2.03 Hz, 1H); 8.36 (s, 1H); 9.04 (s, 1H); 9.06 (s, 1H).

EXAMPLE 2543-{4-amino-5-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 as the trifluoroacetate salt. MS(ESI(+)) m/e 479 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t, J=7.46 Hz,2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H); 6.80 (m, 1H);7.15 (m, 1H); 7.26-7.38 (m, 3H); 7.47-7.55 (m, 1H); 7.64 (d, J=8.81 Hz,2H); 8.34 (s, 1H); 9.03 (s, 1H); 9.05 (s, 1H).

EXAMPLE 2553-{4-amino-5-[4-({[(3-fluoro-4-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-fluoro-4-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 493 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.46 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H);6.80 (m, 1H); 7.15 (m, 1H); 7.33 (m, 3H); 7.51 (m, 1H); 7.64 (d, J=8.81Hz, 2H); 8.34 (s, 1H); 9.03 (s, 1H); 9.05 (s, 1H).

EXAMPLE 2563-{4-amino-5-[4-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-chloro-4-fluorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 513 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.12 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H);7.32-7.38 (m, 4H); 7.65 (d, J=8.48 Hz, 2H); 7.83 (m, 1H); 8.36 (s, 1H);9.06 (s, 1H); 9.08 (s, 1H).

EXAMPLE 2573-(4-amino-5-{4-[(anilinocarbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C forExample 1E in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.29 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz, 2H); 2.89 (s, 3H);6.99 (t, J=7.29 Hz, 1H); 7.30 (m, 2H); 7.34 (d, J=8.48 Hz, 2H); 7.48 (d,J=7.46 Hz, 2H); 7.64 (d, J=8.48 Hz, 2H); 8.34 (s, 1H); 8.79 (s, 1H);8.94 (s, 1H).

EXAMPLE 2583-[4-amino-5-(4-{[(2,3-dihydro-1H-inden-5-ylamino)carbonyl]amino}phenyl)thieno[2,3-d]pyrimidin-6-yl]-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and5-isocyanatoindane for Example 1E and phenyl isocyanate, respectively,in Example 1F. The product was purified by HPLC using the conditionsdescribed in Example 179 to provide the trifluoracetate salt. MS(ESI(+)) m/e 501 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.01 (m, 2H); 2.59(t, J=7.29 Hz, 2H); 2.80 (s, 3H); 2.75-2.90 (m, 6H); 2.89 (s, 3H); 7.14(m, 2H); 7.33 (d, J=8.48 Hz, 2H); 7.39 (s, 1H); 7.63 (d, J=8.81 Hz, 2H);8.33 (s, 1H); 8.65 (s, 1H); 8.89 (s, 1H).

EXAMPLE 2593-{4-amino-5-[4-({[(3-cyanophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 486 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (t,J=7.29 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.12 Hz, 2H); 2.89 (s, 3H);7.36 (d, J=8.81 Hz, 2H); 7.44 (m, 1H); 7.52 (t, J=7.80 Hz, 1H); 7.66 (d,J=8.48 Hz, 2H); 7.70 (m, 1H); 8.00 (t, J=1.70 Hz, 1H); 8.34 (s, 1H);9.15 (s, 1H); 9.19 (s, 1H).

EXAMPLE 2603-(4-amino-5-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 247C and4-fluoro-3-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. The product was purified byHPLC using the conditions described in Example 179 to provide thetrifluoroacetate salt. MS (ESI(+)) m/e 547 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.59 (t, J=7.29 Hz, 2H); 2.80 (s, 3H); 2.86 (t, J=7.46 Hz,2H); 2.89 (s, 3H); 7.36 (d, J=8.48 Hz, 2H); 7.46 (m, 1H); 7.60-7.71 (m,3H); 8.03 (dd, J=6.44, 2.71 Hz, 1H); 8.33 (s, 1H); 9.09 (s, 1H); 9.18(s, 1H).

EXAMPLE 2613-{4-amino-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-methylpropanamideEXAMPLE 261A3-[4-amino-5-(4-aminophenyl)thieno[2,3-d]pyrimidin-6-yl]-N-methylpropanamide

The desired product was prepared by substituting methylaminehydrochloride for dimethylamine hydrochloride in Examples 247A-C. MS(ESI(+)) m/e 328 (M+H)⁺.

EXAMPLE 261B3-{4-amino-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-methylpropanamide

The desired product was prepared by substituting Example 261A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s,3H); 2.36 (t, J=7.46 Hz, 2H); 2.54 (d, J=4.75 Hz, 3H); 2.86 (t, J=7.29Hz, 2H); 6.81 (d, J=7.46 Hz, 1H); 7.17 (t, J=7.80 Hz, 1H); 7.26 (m, 1H);7.29-7.34 (m, 3H); 7.64 (d, J=8.81 Hz, 2H); 7.80 (m, 1H); 8.33 (s, 1H);8.71 (s, 1H); 8.93 (s, 1H).

EXAMPLE 2623-(4-amino-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 261A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 515 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.37 (t,J=7.46 Hz, 2H); 2.55 (d, J=4.75 Hz, 3H); 2.86 (t, J=7.46 Hz, 2H); 7.33(m, 3H); 7.59 (m, 4H); 7.80 (q, J=4.18 Hz, 1H); 8.04 (s, 1H); 8.33 (m,1H); 9.08 (s, 1H); 9.19 (s, 1H).

EXAMPLE 2633-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 261A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. The product was purified byHPLC using the conditions described in Example 179 to provide thetrifluoroacetate salt. MS (ESI(+)) m/e 533 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.36 (t, J=7.63 Hz, 2H); 2.54 (d, J=4.41 Hz, 3H); 2.86 (t,J=7.46 Hz, 2H); 7.35 (d, J=8.48 Hz, 2H); 7.48-7.45 (m, J=4.24, 2.54 Hz,1H); 7.46-7.57 (m, 1H); 7.65 (d, J=8.48 Hz, 2H); 7.80 (m, J=4.75 Hz,1H); 8.32 (s, 1H); 8.63 (dd, J=7.29, 2.20 Hz, 1H); 9.00 (d, J=3.05 Hz,1H); 9.41 (s, 1H).

EXAMPLE 2643-{4-amino-5-[4-({[(3,5-dimethylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-methylpropanamide

The desired product was prepared by substituting Example 261A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 475 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s,6H); 2.36 (t, J=7.63 Hz, 2H); 2.54 (d, J=4.75 Hz, 3H); 2.86 (t, J=7.29Hz, 1H); 2.86 (t, J=7.29 Hz, 2H); 7.09 (s, 2H); 7.31 (d, J=8.48 Hz, 2H);7.63 (d, J=8.81 Hz, 2H); 7.80 (q, J=4.07 Hz, 1H); 8.33 (s, 1H); 8.63 (s,1H); 8.91 (s, 1H).

EXAMPLE 2653-{4-amino-5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-dpyrimidin-6-yl}-N-methylpropanamide

The desired product was prepared by substituting Example 261A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 481 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.37 (t,J=7.46 Hz, 2H); 2.54 (d, J=4.75 Hz, 3H); 2.86 (t, J=7.46 Hz, 2H); 7.04(m, 1H); 7.27-7.35 (m, 4H); 7.65 (d, J=8.81 Hz, 2H); 7.74 (d, J=2.71 Hz,1H); 7.80 (q, J=4.18 Hz, 1H); 8.34 (s, 1H); 9.04 (s, 1H); 9.05 (s, 1H).

EXAMPLE 2663-{4-amino-5-[4-({[(3-bromophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-dpyrimidin-6-yl]-N-methylpropanamide

The desired product was prepared by substituting Example 261A and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. ¹H NMR (300 MHz, DMSO-d₆) δ 2.37 (t, J=7.46 Hz, 2H); 2.55 (d,J=4.75 Hz, 3H); 2.86 (t, J=7.46 Hz, 2H); 7.17 (m, 1H); 7.26 (t, J=7.97Hz, 1H); 7.30-7.37 (m, 3H); 7.65 (d, J=8.48 Hz, 2H); 7.80 (m, 1H); 7.88(t, J=1.86 Hz, 1H); 8.34 (s, 1H); 9.03 (s, 1H); 9.06 (s, 1H).

EXAMPLE 267N-{4-[4-amino-6-(3-methoxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaEXAMPLE 267A5-(4-aminophenyl)-6-(3-methoxypropyl)thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting 1-iodo-4-methoxybutanefor tert-butyl(3-iodopropoxy)dimethylsilane in Examples 104A and 104B.

EXAMPLE 267BN-{4-[4-amino-6-(3-methoxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl}urea

The desired product was prepared by substituting Example 267A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 520 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 1.72-1.82 (m, 2H); 2.66-2.71 (t, 2H, J=7.5 Hz);3.16 (s, 3H); 3.25-3.29 (t, 2H, J=4.2 Hz); 7.32-7.35 (d, 2H, J=8.7 Hz);7.38-7.45 (m, 1H); 7.49-7.55 (t, 1H, J=8.7 Hz); 7.63-7.66 (d, 2H, J=8.4Hz); 8.27 (s, 1H); 8.62-8.65 (dd, 1H, J=2.1, 7.2 Hz); 8.98-8.99 (d, 1H,J=2.7 Hz); 9.39 (s, 1H); MS (ESI(−)) m/e 518 (M−H)⁻.

EXAMPLE 268N-{4-[4-amino-6-(3-methoxypropyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 267A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 448 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.72-1.82 (m 2H); 2.29 (s, 3H); 2.66-2.71 (t, 2H, J=7.2Hz); 3.16 (s, 3H); 3.24-3.29 (t, 2H, J=6.3 Hz); 6.79-6.82 (d, 1H, J=7.2Hz); 7.14-7.19 (t, 1H, J=7.8 Hz); 7.24-7.31 (m 4H); 7.61-7.64 (d, 2H,J=9 Hz); 8.27 (s, 1H); 8.67 (s, 1H); 8.87 (s, 1H).

EXAMPLE 269N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N]-(3-methylphenyl)ureaEXAMPLE 269A5-(4-aminophenyl)-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substitutingN-[4-(2-iodoethyl)phenyl]-N,N-dimethylamine fortert-butyl(3-iodopropoxy)dimethylsilane in Examples 104A and 104B. MS(ESI(+)) m/e 376 (M+H)⁺.

EXAMPLE 269BN-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 269A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 509 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.29 (s, 3H); 2.85 (s, 6H); 3.85(s, 2H); 6.63-6.66 (d,2H, J=9 Hz); 6.79-6.82 (d, 1H, J=7.8 Hz); 6.95-6.98 (d, 2H, J=8.7 Hz);7.14-7.19 (t, 1H, J=7.5 Hz); 7.24-7.31 (m, 2H); 7.35-7.38 (d, 2H, J=9Hz); 7.63-7.66 (d, 2H, J=8.7 Hz); 8.25 (s, 1H); 8.68 (s, 1H); 8.89 (s,1H).

EXAMPLE 270N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 269A and3-trifluomethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 563 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H, J=9 Hz);6.95-6.98 (d, 2H, J=8.7 Hz); 7.32-7.37 (m, 1H); 7.37-7.39 (d, 2H, J=8.7Hz); 7.50-7.56 (t, 1H, J=7.5 Hz); 7.59-7.63 (m, 1H); 7.66-7.68 (d, 2H,J=8.4 Hz); 8.04 (s, 1H); 8.25 (s, 1H); 9.03 (s, 1H); 9.14 (s, 1H).

EXAMPLE 271N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N]-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 269A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 529 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H, J=9 Hz);6.95-6.98 (d, 2H, J=8.7 Hz); 7.02-7.06 (td, 1H, J=2.1, 6.9 Hz);7.30-7.32 (m, 2H); 7.36-7.39 (d, 2H, J=8.4 Hz); 7.64-7.67 (d, 2H, J=8.4Hz); 7.73-7.74 (m, 1H); 8.25 (s, 1H); 8.98 (s, 1H); 8.99 (s, 1H).

EXAMPLE 272N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 269A and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 523 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16-1.21 (t, 3H, J=7.5 Hz); 2.51-2.62 (q, 2H, J=7.2Hz); 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H, J=9 Hz); 6.83-6.85 (m1H); 6.95-6.98 (d, 2H, J=8.7 Hz); 7.17-7.22 (t, 1H, J=7.2 Hz); 7.26-7.29(m, 1H); 7.34-7.38 (m, 3H); 7.64-7.66 (d, 2H, J=8.7 Hz); 8.25 (s, 1H);8.69 (s, 1H); 8.88 (s, 1H).

EXAMPLE 273N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 269A and3-bromophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 573, 575 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H, J=9Hz); 6.95-6.98 (d, 2H, J=8.7 Hz); 7.15-7.18 (td, 1H, J=1.5, 7.8 Hz);7.23-7.28 (t, 1H, J=7.8 Hz); 7.32-7.39 (m, 3H); 7.64-7.67 (d, 2H, J=8.4Hz); 7.87-7.88 (t, 1H, J=1.8 Hz); 8.25 (s, 1H); 8.96 (s, 1H); 8.99 (s,1H).

EXAMPLE 274N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 269A and2-fluoro-5-trifluomethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 581 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H,J=9 Hz); 6.95-6.98 (d, 2H, J=8.7 Hz); 7.38-7.44 (m, 3H); 7.48-7.55 (m,1H); 7.66-7.68 (d, 2H, J=8.4 Hz); 8.25 (s, 1H); 8.62-8.65 (dd, 1H,J=2.4, 7.5 Hz); 8.98-8.99 (d, 1H, J=2.7 Hz); 9.41 (s, 1H).

EXAMPLE 275N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 269A and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 520 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d, 2H, J=9 Hz);6.95-6.98 (d, 2H, J=8.7 Hz); 7.37-7.40 (d, 2H, J=8.7 Hz); 7.42-7.46 (td,1H, J=2.1, 6.6 Hz); 7.48-7.54 (t, 1H, J=7.8 Hz); 7.65-7.73 (m, 3H);7.99-8.00 (t, 1H, J=1.8 Hz); 8.25 (s, 1H); 9.08 (s, 1H); 9.12 (s, 1H).

EXAMPLE 276N-(4-{4-amino-6-[4-(dimethylamino)benzyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 269A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 523 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.24 (s, 6H); 2.85 (s, 6H); 3.85 (s, 2H); 6.63-6.66 (d,3H, J=9 Hz); 6.95-6.98 (d, 2H, J=8.7 Hz); 7.09 (s, 2H); 7.34-7.37 (d,2H, J=9 Hz); 7.63-7.66 (d, 2H, J=8.7 Hz); 8.25 (s, 1H); 8.59 (s, 1H);8.87 (s, 1H).

EXAMPLE 277N-[4-(4-amino-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 277A5-(4-aminophenyl)-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substitutingN-[4-(3-iodopropyl)phenyl]-N,N-dimethylamine fortert-butyl(3-iodopropoxy)dimethylsilane in Examples 104A and 104B. MS(ESI(+)) m/e 390 (M+H)⁺.

EXAMPLE 277BN-[4-(4-amino-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 277A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 523 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.28 (s, 3H); 2.73-2.88 (s and m, 10H); 6.60-6.63 (d,2H, J=9 Hz); 6.79-6.82 (d, 1H, J=7.5 Hz); 6.87-6.90 (d, 2H, J=8.7 Hz);7.09-7.12 (d, 2H, J=6.3 Hz); 7.14-7.19 (t, 1H, J=7.5 Hz); 7.24-7.31 (m,2H); 7.55-7.58 (d, 2H, J=8.4), 8.25 (s, 1H); 8.66 (s, 1H); 8.86 (s, 1H).

EXAMPLE 278N-[4-(4-amino-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl}urea

The desired product was prepared by substituting Example 277A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 577 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.73-2.88 (s and m, 10H); 6.60-6.63 (d, 2H, J=9 Hz);6.87-6.90 (d, 2H, J=8.4 Hz); 7.11-7.14 (d, 2H, J=8.7 Hz); 7.32-7.34 (d,1H, J=6.9 Hz); 7.50-7.60 (m, 4H); 8.03 (s, 1H); 8.26 (s, 1H); 9.01 (s,1H); 9.13 (s, 1H).

EXAMPLE 279N-[4-(4-amino-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 277A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 595 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.73-2.88 (s and m, 10H); 6.60-6.63 (d, 2H, J=9Hz); 6.87-6.90 (d, 2H, J=8.4 Hz); 7.13-7.16 (d, 2H, J=8.7 Hz); 7.38-7.44(m, 1H); 7.48-7.55 (m, 1H); 7.58-7.61 (d, 2H, J=8.7 Hz); 8.26 (s, 1H);8.61-8.65 (dd, 1H, J=2.4, 7.8 Hz); 8.97-8.98 (d, 1H, J=2.7 Hz); 9.38 (s,1H).

EXAMPLE 280N-[4-(4-amino-6-{2-[4-(dimethylamino)phenyl]ethyl}thieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 277A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 537 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.24 (s, 6H); 2.73-2.89 (s and m, 10H); 6.60-6.63 (d,3H, J=9 Hz); 6.87-6.90 (d, 2H, J=7.8 Hz); 7.09-7.12 (d, 4H, J=8.4 Hz);7.55-7.58 (d, 2H, J=8.7 Hz); 8.26 (s, 1H); 8.58 (s, 1H); 8.84 (s, 1H).

EXAMPLE 281N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)ureaEXAMPLE 281AN-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea

A 0° C. solution of 4-hydroxy-1-(4-nitrophenyl)-1-butanone (5.68 g, 29.4mmol, prepared by substituting Example 104A for Example 104C in Example104D] in dichloromethane (60 mL) was treated with triethylamine (4.9 mL,35 mmol), CH₃SO₂Cl (2.7 mL, 35 mmol), stirred at 0° C. for 3 hours,poured into water, and extracted three times with dichloromethane. Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The concentrate was purified by silica gel chromatographywith 50% ethyl acetate/hexanes to provide 6.42 g (76% yield) of thedesired product. R_(f) (50% ethyl acetate/hexanes)=0.2.

EXAMPLE 281B 4-(dimethylamino)-1-(4-nitrophenyl)-1-butanone

A mixture of Example 281A (3 g, 10.5 mmol), dimethylamine (21 mL, 2M inTHF), and triethylamine (2.9 mL, 21 mmol) in DMF (25 mL) was heated to85-90° C. for 1.5 hours, cooled to room temperature, diluted with water,and extracted twice with ethyl acetate. The combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by silica gel chromatography eluting with 10%methanol/dichloromethane to provide 1.27 g (51% yield) of the desiredproduct. MS (ESI(+)) m/e 237 (M+H)⁺.

EXAMPLE 281C2-amino-5-[2-(dimethylamino)ethyl]-4-(4-nitrophenyl)-3-thiophenecarbonitrile

The desired product was prepared by substituting Example 281B forExample 1A in Examples 1B-C. MS ((ESI(+)) m/e 317 (M+H)⁺.

EXAMPLE 281D AND 281 E6-[2-(dimethylamino)ethyl]-5-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4-amineand 5-(4-nitrophenyl)-6-vinylthieno[2,3-d]pyrimidin-4-amine

A solution of Example 281C (100 mg) in formamide (3 mL) in a 5 mL cappedvial was heated to 200° C. for 15 minutes in a Smith Synthesizermicrowave oven at 300 W. The reaction was repeated 10 times. Thecombined solutions were diluted with water and extracted twice withethyl acetate. The combined extracts were washed with brine, dried(Na₂SO₄), filtered, and concentrated. The residue was purified by silicagel chromatography with 7% methanol/dichloromethane to provide 0.73 g(59% yield) of Example 281D, and 0.28 g (26% yield) of Example 281E.Example 281D: MS ((ESI(+)) m/e 344 (M+H)⁺; Example 281E: MS ((ESI(+))m/e 299 (M+H)⁺.

EXAMPLE 281F5-(4-aminophenyl)-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 281D forExample 1D in Example 1E. MS ((ESI(+)) m/e 314 (M+H)⁺.

EXAMPLE 281GN-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 281F and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 447 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.11 (s, 6H); 2.29 (s, 3H); 2.42-2.46 (t, 2H, J=7.2 Hz);2.72-2.77 (t, 2H, J=6 Hz); 6.79-6.82 (d, 1H, J=7.5 Hz); 7.14-7.19 (t,1H, J=7.5 Hz); 7.24-7.32 (m, 4H); 7.61-7.64 (d, 2H, J=6.6 Hz); 8.26 (s,1H); 8.67 (s, 1H); 8.87 (s, 1H).

EXAMPLE 282N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 281F and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 501 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.10 (s, 6H); 2.41-2.46 (t, 2H, J=7.2 Hz); 2.72-2.77 (t,2H, J=6 Hz); 7.31-7.34 (m, 3H); 7.50-7.56 (t, 1H, J=7.2 Hz); 7.59-7.67(m, 3H); 8.03 (br s, 1H); 8.26 (s, 1H); 9.02 (s, 1H); 9.14 (s, 1H).

EXAMPLE 283N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 281F and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16-1.21 (t, 3H, J=7.5 Hz); 2.11 (s, 6H); 2.41-2.46 (t,2H, J=7.2 Hz); 2.55-2.62 (q, 2H, J=7.5 Hz); 2.72-2.77 (t, 2H, J=6 Hz);6.83-6.85 (d, 1H, J=7.5 Hz); 7.17-7.22 (t, 1H, J=7.5 Hz); 7.26-7.34 (m,4H); 7.61-7.64 (d, 2H, J=8.4 Hz); 8.26 (s, 1H); 8.69 (s, 1H); 8.88 (s,1H).

EXAMPLE 284N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 281F and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 519 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.10 (s, 6H); 2.41-2.46 (t, 2H, J=7.2 Hz);2.72-2.77 (t, 2H, J=6 Hz); 7.33-7.36 (d, 2H, J=8.7 Hz); 7.41-7.55 (m,2H); 7.63-7.66 (d, 2H, J=8.4 Hz); 8.26 (s, 1H); 8.62-8.65 (dd, 1H,J=1.8, 6.9 Hz); 8.98-8.99 (d, 1H, J=2.7 Hz); 9.39 (s, 1H).

EXAMPLE 285N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 281F and3-cyanophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 458 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.11 (s, 6H); 2.42-2.47 (t, 2H, J=7.2 Hz); 2.73-2.77 (t,2H, J=7.2 Hz); 7.32-7.34 (d, 2H, J=8.1 Hz); 7.42-7.46 (td, 1H, J=1.5,7.2 Hz); 7.49-7.54 (t, 1H, J=7.8 Hz); 7.63-7.66 (d, 2H, J=8.4 Hz);7.68-7.72 (td, 1H, J=1.2, 9.3 Hz); 7.99-8.00 (t, 1H, J=2.4 Hz); 8.26 (s,1H); 9.11 (s, 1H); 9.16 (s, 1H).

EXAMPLE 286N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 281F and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 485 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.12 (s, 6H); 2.28 (s, 3H); 2.73-2.76 (t, 2H, J=3.5 Hz);6.78-6.86 (m 1H); 7.09-7.15 (dd, 1H, J=8.47, 11.4 Hz); 7.30-7.33 (d, 2H,J=8.4 Hz); 7.61-7.64 (d, 2H, J=8.7 Hz); 7.98-9.01 (d, 1H, J=2.1, 8.1Hz); 8.26 (s, 1H); 8.56-8.57 (d, 1H, J=2.4 Hz); 9.29 (s, 1H).

EXAMPLE 287N-[4-(4-amino-6-vinylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 287A 5-(4-aminophenyl)-6-vinylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 281E forExample 1D in Example 1E. MS ((ESI(+)) m/e 269 (M+H)⁺.

EXAMPLE 287BN-[4-(4-amino-6-vinylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 287A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 402 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.29 (s, 3H); 5.28-5.32 (d, 1H, J=11.4 Hz); 5.59-5.64(d, 1H, J=17.1 Hz); 6.50-6.60 (dd, 1H, J=10.8, 17.1 Hz); 6.80-6.82 (d,1H, J=7.5 Hz); 7.14-7.20 (t, 1H, J=7.8 Hz); 7.24-7.27 (d, 1H, J=8.4 Hz);7.30-7.33 (m, 3H); 7.63-7.66 (d, 2H, J=8.4 Hz); 8.31 (s, 1H); 8.68 (s,1H); 8.91 (s, 1H).

EXAMPLE 288N-[4-(4-amino-6-vinylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 287A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 474 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 5.29-5.32 (d, 1H, J=11.1 Hz); 5.59-5.65 (d, 1H,J=17.1 Hz); 6.50-6.59 (dd, 1H, J=10.8, 17.1 Hz); 7.34-7.37 (d, 2H, J=8.4Hz); 7.38-7.45 (m, 1H); 7.49-7.55 (t, 1H, J=8.7 Hz); 7.65-7.68 (d, 2H,J=8.4 Hz); 8.31 (s, 1H); 8.62-8.65 (dd, 1H, J=2.1, 7.2 Hz); 8.98-8.99(d, 1H, J=2.7 Hz); 9.43 (s, 1H).

EXAMPLE 289N-[4-(4-amino-6-vinylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 287A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 456 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 5.29-5.33 (d, 1H, J=11.1 Hz); 5.59-5.65 (d, 1H, J=17.4Hz); 6.50-6.60 (dd, 1H, J=10.8, 17.4 Hz); 7.32-7.35 (m, 3H); 7.51-7.56(t, 1H, J=7.5 Hz); 7.59-6.25 (m, 1H); 7.65-7.68 (d, 2H, J=8.4 Hz); 8.04(s, 1H); 8.31 (s, 1H); 9.07 (s, 1H); 9.15 (s, 1H).

EXAMPLE 290N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)ureaEXAMPLE 290A 5-(4-aminophenyl)-6-propylthieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting n-butyl iodide fortert-butyl(3-iodopropoxy)dimethylsilane in Examples 104A and B. ¹H NMR(300 MHz, DMSO-d₆) δ 0.84 (t, J=7.46 Hz, 3H); 1.50-1.60 (m, 2H); 2.60(t, J=7.46 Hz, 2H); 5.39 (s, 2H); 6.69 (d, J=8.48 Hz, 2H); 6.99 (d,J=8.48 Hz, 2H); 8.23 (s, 1H).

EXAMPLE 290BN-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 290A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 438 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.84 (t, J=7.29 Hz, 3H); 1.50-1.68 (m, 2H); 2.61 (t,J=7.46 Hz, 2H); 7.04 (dt, J=6.53, 2.33 Hz, 1H); 7.31 (m, 4H); 7.63 (d,J=8.81 Hz, 2H); 7.73 (m, 1H); 8.27 (s, 1H); 8.96 (s, 2H).

EXAMPLE 291N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 290A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 418 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.85 (t, J=7.29 Hz, 3H); 1.50-1.68 (m, 2H); 2.29 (s,3H); 2.61 (t, J=7.63 Hz, 2H); 6.81 (d, J=7.80 Hz, 1H); 7.24 (m, 5H);7.62 (d, J=8.48 Hz, 2H); 8.26 (s, 1H); 8.67 (s, 1H); 8.87 (s, 1H).

EXAMPLE 292N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 290A and3-ethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 432 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.85 (t, J=7.29 Hz, 3H); 1.19 (t, J=7.46 Hz, 3H); 1.58(q, J=7.50 2H); 2.45-2.70 (m, 4H); 6.84 (d, J=7.46 Hz, 1H); 7.15-7.40(m, 5H); 7.62 (d, J=8.48 Hz, 2H); 8.27 (s, 1H); 8.69 (s, 1H); 8.87 (s,1H).

EXAMPLE 293N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 290A and4-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 472 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.85 (t, J=7.29, 3H); 1.50-1.68 (m, J=6.78 Hz, 2H); 2.61(t, J=7.80 Hz, 2H); 7.32 (d, J=8.48 Hz, 2H); 7.60-7.7.78 (m, 6H); 8.27(s, 1H); 9.03 (s, 1H); 9.19 (s, 1H).

EXAMPLE 294N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 290A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 472 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.85 (t, J=7.29 Hz, 3H); 1.50-1.68 (m, 2H); 2.62 (t,J=7.46 Hz, 2H); 7.30-7.40 (m, 3H); 7.50-7.80 (m, 4H); 8.04 (s, 1H); 8.27(s, 1H); 9.01 (s, 1H); 9.13 (s, 1H).

EXAMPLE 295N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 290A forExample 1E in Example 1F. MS (ESI(+)) m/e 404 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 0.85 (t, J=7.29 Hz, 3H); 1.50-1.68 (m, 2H); 2.62 (t, J=7.46Hz, 2H); 6.99 (t, J=7.29 Hz, 1H); 7.30 (m, 4H); 7.47 (d, J=7.46 Hz, 2H);7.63 (d, J=8.48 Hz, 2H); 8.27 (s, 1H); 8.75 (s, 1H); 8.89 (s, 1H).

EXAMPLE 296N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-cyclohexylurea

The desired product was prepared by substituting Example 290A andisocyanatocyclohexane for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 410 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.83 (t, J=7.29 Hz, 3H); 1.00-1.90 (m, 13H); 2.59 (t,J=7.80 Hz, 2H); 6.17 (d, J=7.80 Hz, 1H); 7.22 (d, J=8.48 Hz, 2H); 7.54(d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.53 (s, 1H).

EXAMPLE 297N-[4-(4-amino-6-propylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-phenoxyphenyl)urea

The desired product was prepared by substituting Example 290A and3-phenoxyphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 496 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 0.84 (t, J=7.46 Hz, 3H); 1.45-1.55 (m, 2H); 2.60 (t,J=7.46 Hz, 2H); 6.63 (dd, J=8.14, 1.70 Hz, 1H); 7.00-7.50 (m, 10H); 7.59(d, J=8.48 Hz, 2H); 8.26 (s, 1H); 8.86 (s, 1H); 8.88 (s, 1H).

EXAMPLE 298N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 78A for Example1E in Example 1F. MS (ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 1.17 (t, J=7.63 Hz, 3H); 2.66 (q, J=7.46 Hz, 2H); 6.99 (t, J=7.46 Hz,1H); 7.30 (t, J=8.48 Hz, 4H); 7.48 (d, J=7.46 Hz, 2H); 7.63 (d, J=8.48Hz, 2H); 8.29 (s, 1H); 8.78 (s, 1H); 8.93 (s, 1H).

EXAMPLE 299N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-cyclohexylurea

The desired product was prepared by substituting Example 78A andisocyanatocyclohexane for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 396 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.00-1.90 (m, 14H); 2.63 (q, J=7.69 Hz, 2H); 6.17 (d,J=7.80 Hz, 1H); 7.23 (d, J=8.48 Hz, 2H); 7.54 (d, J=8.48 Hz, 2H); 8.27(s, 1H); 8.54 (s, 1H).

EXAMPLE 300N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(dimethylamino)phenyl]urea

The desired product was prepared by substituting Example 78A and4-dimethylaminoaniline for Example 58D and 3-methylbutylamine,respectively, in Example 179. MS (ESI(+)) m/e 433 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.16 (t, J=7.46 Hz, 3H); 2.65 (q, J=7.35 Hz, 2H); 2.84(s, 6H); 6.71 (d, J=8.82 Hz, 2H); 7.27 (d, J=2.37 Hz, 2H); 7.30 (d,J=2.03 Hz, 2H); 7.61 (d, J=8.48 Hz, 2H); 8.26 (s, 1H); 8.38 (s, 1H);8.76 (s, 1H).

EXAMPLE 301N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-{4-[2-(dimethylamino)ethyl]phenyl}urea

The desired product was prepared by substituting Example 78A and4-[2-(dimethylamino)ethyl]aniline for Example 58D and3-methylbutylamine, respectively, in Example 179. MS (ESI(+)) m/e 461(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.16 (t, J=7.63 Hz, 3H); 2.47 (s,6H); 2.65 (m, 2H); 2.70-2.90 (m, 4H); 7.17 (d, J=8.81 Hz, 2H); 7.30 (d,J=8.48 Hz, 2H); 7.41 (d, J=8.48 Hz, 2H); 7.62 (d, J=8.48 Hz, 2H); 8.26(s, 1H); 8.87 (s, 1H); 9.06 (s, 1H).

EXAMPLE 302N-[4-(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 97 and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS(ESI(+)) m/e 395 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 2.28 (s, 3H); 6.75-6.90 (m, 1H); 7.05-7.20 (m, 1H); 7.55-7.70(m, 4H); 7.95-8.05 (m, 1H); 8.47 (s, 1H); 8.58 (s, 1H); 9.35 (s, 1H).

EXAMPLE 3033-{4-amino-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-[2-(diethylamino)ethyl]propanamideEXAMPLE 303A3-[4-amino-5-(4-aminophenyl)thieno[2,3-d]pyrimidin-6-yl]-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substitutingN,N-diethylethylenediamine for dimethylamine hydrochloride in Examples247A-B. MS (ESI(+)) m/e 413 (M+H)⁺.

EXAMPLE 303B3-{4-amino-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 546 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t,J=7.29 Hz, 6H); 2.29 (s, 3H); 2.43 (t, J=7.46 Hz, 2H); 2.89 (t, J=7.46Hz, 2H); 3.00-3.20 (m, 6H); 3.32-3.42 (m, 2H); 6.81 (d, J=6.78 Hz, 1H);7.17 (t, J=7.63 Hz, 1H); 7.25-7.35 (m, 4H); 7.60-7.68 (m, 2H); 8.19 (t,J=5.76 Hz, 1H); 8.29 (s, 1H); 8.84 (s, 1H); 9.06 (s, 1H).

EXAMPLE 3043-{4-amino-5-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and3-chlorophenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 566 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t,J=7.29 Hz, 6H); 2.43 (t, J=7.63 Hz, 2H); 2.89 (t, J=7.29 Hz, 2H);3.00-3.20 (m, 6H); 3.37 (q, J=5.99 Hz, 2H); 6.95-7.08 (m, 1H); 7.25-7.38(m, 4H); 7.66 (d, J=8.48 Hz, 2H); 7.72-7.78 (m, 1H); 8.19 (t, J=5.76 Hz,1H); 8.29 (s, 1H); 9.26 (s, 1H); 9.27 (s, 1H).

EXAMPLE 3053-(4-amino-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 600 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.15 (t, J=7.29 Hz, 6H); 2.43 (t, J=7.29 Hz, 2H); 2.89(t, J=7.29 Hz, 2H); 3.00-3.20 (m, 6H); 3.30-3.45 (m, 2H); 7.33 (d,J=8.48 Hz, 3H); 7.45-7.65 (m, 2H); 7.67 (d, J=8.48 Hz, 2H); 8.06 (s,1H); 8.19 (t, J=5.76 Hz, 1H); 8.29 (s, 1H); 9.31 (s, 1H); 9.42 (s, 1H).

EXAMPLE 3063-{4-amino-5-[4-({[(3,5-dimethylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and3,5-dimethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 560 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t,J=7.29 Hz, 6H); 2.24 (s, 6H); 2.43 (t, J=7.46 Hz, 2H); 2.89 (t, J=7.46Hz, 2H); 3.00-3.20 (m, 6H); 3.32-3.42 (m, 2H); 6.63 (s, 1H); 7.11 (s,2H); 7.31 (d, J=8.48 Hz, 2H); 7.65 (d, J=8.82 Hz, 2H); 8.20 (t, J=5.26Hz, 1H); 8.30 (s, 1H); 8.83 (s, 1H); 9.12 (s, 1H).

EXAMPLE 3073-{4-amino-5-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[2,3-d]pyrimidin-6-yl}-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and2-fluoro-5-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. The product was purified by HPLC using theconditions described in Example 179 to provide the trifluoroacetatesalt. MS (ESI(+)) m/e 564 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t,J=7.29 Hz, 6H); 2.28 (s, 3H); 2.43 (t, J=7.63 Hz, 2H); 2.89 (t, J=7.63Hz, 2H); 3.00-3.20 (m, 6H); 3.32-3.42 (m, 2H); 6.78-6.88 (m, 1H); 7.12(dd, J=11.53, 8.48 Hz, 1H); 7.33 (d, J=8.48 Hz, 2H); 7.64 (d, J=8.81 Hz,2H); 7.98 (dd, J=7.46, 2.03 Hz, 1H); 8.19 (t, J=5.59 Hz, 1H); 8.29 (s,1H); 8.60 (d, J=2.37 Hz, 1H); 9.34 (s, 1H).

EXAMPLE 3083-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-6-yl)-N-[2-(diethylamino)ethyl]propanamide

The desired product was prepared by substituting Example 303A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 618 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 1.16 (t, J=7.29 Hz, 6H); 2.43(t, J=7.63 Hz,2H); 2.89 (t, J=7.63 Hz, 2H); 3.00-3.20 (m, 6H); 3.32-3.42 (m, 2H); 7.36(d, J=8.48 Hz, 2H); 7.36-7.60 (m, 2H); 7.67 (d, J=8.48 Hz, 2H); 8.27 (t,J=5.60 Hz, 1H); 8.31 (s, 1H); 8.63 (dd, J=7.29, 2.20 Hz, 1H); 9.14 (d,J=2.03 Hz, 1H); 9.75 (s, 1H).

Examples 309-334 were synthesized in an automated parallel fashion asfollows: Example 78A (10 mg, 0.04 mmol) was dissolved in dichloromethane(2 mL) and added to a reaction vessel containing PS-diethylamine (23mg). The solution was treated with a solution ofp-nitrophenylchloroformate (9 mg) in dichloromethane (1 mL), mixed for 2hours, treated with a solution of the desired amine (0.06 mmol), mixedfor 16 hours, treated with the scavenger resins PS-trisamine (12 mg) andPS-isocyanate (12 mg), and concentrated. The product was purified byHPLC using the conditions described in Example 179.

EXAMPLE 309N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-ethylphenyl)urea

Amine: 4-ethylaniline. MS (ESI(+)) m/e 418 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.16 (t, J=7.64 Hz, 6H); 2.55 (q, J=7.49 Hz, 2H); 2.65 (q,J=7.70 Hz, 2H); 7.13 (d, J=8.42 Hz, 2H); 7.30 (d, J=8.73 Hz, 2H); 7.37(d, J=8.42 Hz, 2H); 7.62 (d, J=8.73 Hz, 2H); 8.28 (s, 1H); 8.65 (s, 1H);8.86 (s, 1H).

EXAMPLE 310N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-isopropylphenyl)urea

Amine: 4-isopropylaniline. MS (ESI(+)) m/e 432 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.10-1.25 (m, 9H); 2.65 (q, J=7.49 Hz, 2H); 2.84 (m, 1H);7.16 (d, J=8.42 Hz, 2H); 7.30 (d, J=8.42 Hz, 2H); 7.38 (d, J=8.42 Hz,2H); 7.62 (d, J=8.42 Hz, 2H); 8.28 (s, 1H); 8.65 (s, 1H); 8.85 (s, 1H).

EXAMPLE 311N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-tert-butylphenyl)urea

Amine: 3-tert-butylaniline. MS (ESI(+)) m/e 446 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 1.28 (s, 9H); 2.66 (q, J=7.49 Hz,2H); 7.03 (d, J=7.80 Hz, 1H); 7.21 (t, J=7.96 Hz, 1H); 7.31 (d, J=8.73Hz, 3H); 7.48 (t, J=1.87 Hz, 1H); 7.63 (d, J=8.42 Hz, 2H); 8.29 (s, 1H);8.73 (s, 1H); 8.86 (s, 1H).

EXAMPLE 312N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-tert-butylphenyl)urea

Amine: 4-tert-butylaniline. MS (ESI(+)) m/e 446 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.15 (t, J=7.49 Hz, 3H); 1.26 (s, 9H); 2.64 (q, J=7.49 Hz,2H); 7.25-7.32 (m, 4H); 7.35-7.40 (m, 2H); 7.56-7.65 (m, 2H); 8.27 (s,1H); 8.65 (s, 1H); 8.84 (s, 1H).

EXAMPLE 313N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea

Amine: 2-methyl-3-fluoroaniline. MS (ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.17 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 6.88 (t, J=8.89 Hz, 1H); 7.15-7.25 (m, 1H); 7.32 (d, J=8.42 Hz,2H); 7.60-7.72(m, 3H); 8.19 (s, 1H); 8.28 (s, 1H); 9.27 (s, 1H).

EXAMPLE 314N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-fluoro-4-methylphenyl)urea

Amine: 2-fluoro-4-methylaniline. MS (ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.32 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 6.96 (d, J=9.36 Hz, 1H); 7.07 (d, J=12.17 Hz, 1H); 7.25-7.35(m, 2H); 7.55-7.65 (m, 2H); 7.98 (t, J=8.58 Hz, 1H); 8.28 (s, 1H); 8.50(d, J=2.18 Hz, 1H); 9.22 (s, 1H).

EXAMPLE 315N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluoro-5-methylphenyl)urea

Amine: 3-fluoro-5-methylaniline. MS (ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.30 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 7.05 (dd, J=8.27, 2.03 Hz, 1H); 7.17 (t, J=8.73 Hz, 1H); 7.31(d, J=8.73 Hz, 2H); 7.44 (dd, J=12.48, 2.18 Hz, 1H); 7.62 (d, J=8.74 Hz,2H); 8.27 (s, 1H); 8.89 (s, 1H); 8.95 (s, 1H).

EXAMPLE 316N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-fluoro-2-methylphenyl)urea

Amine: 4-fluoro-2-methylaniline. MS (ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.28 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 6.99 (td, J=8.73, 3.12 Hz, 1H); 7.08 (dd, J=9.51, 2.96 Hz, 1H);7.30 (d, J=8.42 Hz, 2H); 7.63 (d, J=8.42 Hz, 2H); 7.72 (dd, J=8.73, 5.62Hz, 1H); 8.02 (s, 1H); 8.27 (s, 1H); 9.17 (s, 1H).

EXAMPLE 317N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea

Amine: 4-fluoro-3-methylaniline. MS (ESI(+)) m/e 422 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.30 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 7.06 (t, J=9.20 Hz, 1H); 7.25-7.35 (m, J=8.42 Hz, 3H); 7.37(dd, J=6.86, 2.50 Hz, 1H); 7.62 (d, J=8.42 Hz, 2H); 8.28 (s, 1H); 8.71(s, 1H); 8.90 (s, 1H).

EXAMPLE 318N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chloro-4-methylphenyl)urea

Amine: 3-chloro-4-methylaniline. MS (ESI(+)) m/e 438 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.27 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 7.20-7.30 (m, 2H); 7.31 (d, J=8.42 Hz, 2H); 7.63 (d, J=8.42 Hz,2H); 7.71 (d, J=1.87 Hz, 1H); 8.29 (s, 1H); 8.88 (s, 1H); 8.96 (s, 1H).

EXAMPLE 319N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-chloro-3-methylphenyl)urea

Amine: 4-chloro-3-methylaniline. MS (ESI(+)) m/e 438 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.31 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 7.20-7.40 (m, 4H); 7.46 (d, J=2.50 Hz, 1H); 7.63 (d, J=8.73 Hz,2H); 8.28 (s, 1H); 8.83 (s, 1H); 8.94 (s, 1H).

EXAMPLE 320N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-bromo-4-methylphenyl)urea

Amine: 3-bromo-4-methylaniline. MS (ESI(+)) m/e 482, 484 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.17 (t, J=7.64 Hz, 3H); 2.29 (s, 3H); 2.65 (q,J=7.59 Hz, 2H); 7.26 (d, J=0.94 Hz, 2H); 7.31 (d, J=8.73 Hz, 2H); 7.63(d, J=8.73 Hz, 2H); 7.88 (s, 1H); 8.29 (s, 1H); 8.87 (s, 1H); 8.96 (s,1H).

EXAMPLE 321N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(4-bromo-3-methylphenyl)urea

Amine: 4-bromo-3-methylaniline. MS (ESI(+)) m/e 482, 484 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.33 (s, 3H); 2.65 (q,J=7.70 Hz, 2H); 7.25-7.35 (m, 3H); 7.40-7.55 (m, 2H); 7.63 (d, J=8.73Hz, 2H); 8.29 (s, 1H); 8.84 (s, 1H); 8.95 (s, 1H).

EXAMPLE 322N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-fluoro-4-methoxyphenyl)urea

Amine: 3-fluoro-4-methoxyaniline. MS (ESI(+)) m/e 438 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.65 (q, J=7.49 Hz, 2H);3.80 (s, 3H); 7.05-7.15 (m, J=1.87 Hz, 2H); 7.31 (d, J=8.42 Hz, 2H);7.45-7.55 (m, 1H); 7.62 (d, J=8.73 Hz, 2H); 8.29 (s, 1H); 8.78 (s, 1H);8.91 (s, 1H).

EXAMPLE 323N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-methoxy-5-(trifluoromethyl)phenyl]urea

Amine: 3-methoxy-5-trifluoromethylaniline. MS (ESI(+)) m/e 488 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.65 (q, J=7.49 Hz,2H); 3.83 (s, 3H); 6.86 (s, 1H); 7.25-7.35 (m, 3H); 7.50 (s, 1H); 7.64(d, J=8.42 Hz, 2H); 8.28 (s, 1H); 9.04 (s, 1H); 9.15 (s, 1H).

EXAMPLE 324N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(hydroxymethyl)phenyl]urea

Amine: 4-hydroxymethylaniline. MS (ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.26 (t, J=6.86 Hz, 3H); 2.65 (q, J=7.49 Hz, 2H); 4.43(s, 2H); 7.23 (d, J=8.42 Hz, 2H); 7.30 (d, J=8.73 Hz, 2H); 7.42 (d,J=8.42 Hz, 2H); 7.63 (d, J=8.73 Hz, 2H); 8.27 (s, 1H); 8.73 (s, 1H);8.90 (s, 1H).

EXAMPLE 325N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-methoxy-4-methylphenyl)urea

Amine: 2-methoxy-4-methylaniline. MS (ESI(+)) m/e 434 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.24 (s, 3H); 2.66 (q,J=7.49 Hz, 2H); 3.86 (s, 3H); 6.76 (m, J=7.80, 1.87 Hz, 1H); 6.91 (d,J=8.11 Hz, 1H); 7.31 (d, J=8.42 Hz, 2H); 7.63 (d, J=8.74 Hz, 2H); 8.00(d, J=2.18 Hz, 1H); 8.23 (s, 1H); 8.29 (s, 1H); 9.52 (s, 1H).

EXAMPLE 326N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(2-ethoxyphenyl)urea

Amine: 2-ethoxyaniline. MS (ESI(+)) m/e 434 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 1.43 (t, J=7.02 Hz, 3H); 2.66 (q,J=7.49 Hz, 2H); 4.16 (q, J=7.07 Hz, 2H); 6.85-6.98 (m, 2H); 7.00-7.05(m, 1H); 7.31 (d, J=8.42 Hz, 2H); 7.64 (d, J=8.42 Hz, 2H); 8.12-8.17 (m,2H); 8.28 (s, 1H); 9.61 (s, 1H).

EXAMPLE 327N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(methylsulfanyl)phenyl]urea

Amine: 4-(methylsulfanyl)aniline. MS (ESI(+)) m/e 436 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.16 (t, J=7.33 Hz, 3H); 2.44 (s, 3H); 2.60-2.70(m, J=7.49 Hz, 2H); 7.24 (d, J=8.73 Hz, 2H); 7.31 (d, J=8.73 Hz, 2H);7.44 (d, J=8.73 Hz, 2H); 7.62 (d, J=8.73 Hz, 2H); 8.28 (s, 1H); 8.79 (s,1H); 8.90 (s, 1H).

EXAMPLE 328N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[3-(methylsulfanyl)phenyl]urea

Amine: 3-(methylsulfanyl)aniline. MS (ESI(+)) m/e 436 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.47 (s, 3H); 2.65 (q,J=7.49 Hz, 2H); 6.88 (d, J=8.74 Hz, 1H); 7.22 (m, J=7.80 Hz, 2H); 7.31(d, J=8.73 Hz, 2H); 7.40-7.55 (m, 1H); 7.63 (d, J=8.73 Hz, 2H); 8.28 (s,1H); 8.81 (s, 1H); 8.92 (s, 1H).

EXAMPLE 329N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-2,3-dihydro-1,4-benzodioxin-6-ylurea

Amine: 2,3-dihydro-1,4-benzodioxin-6-amine. MS (ESI(+)) m/e 448 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 1.16 (t, J=7.64 Hz, 3H); 2.65 (q, J=7.49 Hz,2H); 4.10-4.30 (m, 4H); 6.65-6.85 (m, 2H); 7.11 (d, J=2.50 Hz, 1H); 7.30(d, J=8.73 Hz, 2H); 7.61 (d, J=8.73 Hz, 2H); 8.29 (s, 1H); 8.58 (s, 1H);8.83 (s, 1H).

EXAMPLE 330N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-{4-[(4-methoxyphenyl)amino]phenyl}urea

Amine: N-(4-aminophenyl)-N-(4-methoxyphenyl)amine; MS (ESI(+)) m/e 511(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.17 (t, J=7.49 Hz, 3H); 2.65 (q,J=7.59 Hz, 2H); 3.70 (s, 3H); 6.84 (d, J=8.74 Hz, 2H); 6.91 (d, J=8.73Hz, 2H); 6.98 (d, J=8.74 Hz, 2H); 7.25-7.33 (m, 4H); 7.61 (d, J=8.42 Hz,2H); 8.27 (s, 1H); 8.46 (s, 1H); 8.78 (s, 1H).

EXAMPLE 331N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(5-chloro-2,4-dimethoxyphenyl)urea

Amine: 5-chloro-2,4-dimethoxyaniline. MS (ESI(+)) m/e 484 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.65 (q, J=7.49 Hz, 2H);3.86 (s, 3H); 3.95 (s, 3H); 6.88 (s, 1H); 7.31 (d, J=8.74 Hz, 2H); 7.61(d, J=8.42 Hz, 2H); 8.16 (s, 1H); 8.23 (s, 1H); 8.28 (s, 1H); 9.45 (s,1H).

EXAMPLE 332N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-6-quinolinylurea

Amine: 6-quinolinamine. MS (ESI(+)) m/e 441 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 1.16(t, J=7.49, 3H); 2.67 (q, J=7.49 Hz, 2H); 7.34 (d, J=8.42Hz, 2H); 7.52 (dd, J=8.42, 4.37 Hz, 1H); 7.68 (d, J=8.42 Hz, 2H); 7.78(dd, J=9.05, 2.50 Hz, 1H); 7.98 (d, J=9.05 Hz, 1H); 8.23 (d, J=2.18 Hz,1H); 8.28 (s, 1H); 8.34 (d, J=8.73 Hz, 1H); 8.79 (dd, J=4.06, 1.25 Hz,1H); 9.10 (s, 1H); 9.22 (s, 1H).

EXAMPLE 333N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[4-(4-morpholinyl)phenyl]urea

Amine: 4-(4-morpholinyl)aniline. MS (ESI(+)) m/e 475 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.17 (t, J=7.02 Hz, 3H); 2.66 (q, J=7.59 Hz, 2H); 3.07(m, 4H); 3.75 (m, 4H); 7.30 (d, J=8.73 Hz, 2H); 7.36 (d, J=9.05 Hz, 2H);7.63 (d, J=8.73 Hz, 2H); 8.10-8.14 (m, 2H); 8.32 (s, 1H); 8.60 (s, 1H);8.89 (s, 1H).

EXAMPLE 334N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-hydroxy-4-methylphenyl)urea

Amine: 5-amino-2-methylphenol. MS (ESI(+)) m/e 420 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 1.16 (t, J=7.49 Hz, 3H); 2.05 (s, 3H); 2.65 (q, J=7.49Hz, 2H); 6.73 (dd, J=7.96, 2.03 Hz, 1H); 6.88-6.95 (m, 1H); 7.08 (d,J=1.87 Hz, 1H); 7.29 (d, J=8.42 Hz, 2H); 7.61 (d, J=8.73 Hz, 2H); 8.28(s, 1H); 8.56 (s, 1H); 8.80 (s, 1H).

EXAMPLE 3351-[4-(4-amino-6-methylthieno[2,3-d]pyrimidin-5-yl)phenyl]-3-phenylacetone

A mixture of Example 66A (100 mg, 0.31 mmol), 2-propynylbenzene (0.042mL, 0.34 mmol), Pd(PPh₃)₂Cl₂ (11 mg, 0.016 mmol), CuI (3 mg, 0.016mmol), diethylamine (0.48 mL, 4.68 mmol), and triphenylphosphine (16 mg,0.062 mmol) in DMF (0.5 mL) in capped 5 mL vial was stirred whileheating to 120° C. for 25 minutes in a Smith Synthesizer microwave at300 W. The mixture cooled using 40 psi pressurized air, diluted withwater, and extracted three times with ethyl acetate. The combinedextracts were washed with water and brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by silica gel chromatographywith ethyl acetate to provide 38 mg of the desired product. MS (ESI(+))m/e 374 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 3.91 (s, 2H);3.97 (s, 2H); 7.16-7.36 (m, 9H); 8.27 (s, 1H).

EXAMPLE 3366-methyl-5-[4-(3-phenoxy-1-propynyl)phenyl]thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting (2-propynyloxy)benzenefor 2-propynylbenzene in Example 335. MS (ESI(+)) m/e 372 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 5.09 (s, 2H); 6.99 (t, J=7.29 Hz,1H); 7.07 (d, J=7.80 Hz, 2H); 7.35 (m, 2H); 7.41 (d, J=8.14 Hz, 2H);7.60 (d, J=8.48 Hz, 2H); 8.27 (s, 1H).

EXAMPLE 337N-[4-(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 337A 5-(4-nitrophenyl)thieno[2,3-d]pyrimidine-2,4-diamine

A suspension of Example 58B (1 g, 4.08 mmol) and chloroformamidinehydrochloride (1.17 g, 10.2 mmol) in diglyme (40 mL) was heated to 130°C. for 15 hours. The mixture was cooled to room temperature, dilutedwith water, and extracted twice with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was further concentrated under a stream ofnitrogen, and purified by silica gel chromatography with 5 to 7%methanol/dichloromethane to provide 0.26 g of the desired product. MS(ESI(+)) m/e 288 (M+H)⁺.

EXAMPLE 337B 5-(4-aminophenyl)thieno[2,3-d]pyrimidine-2,4-diamine

A suspension of Example 337A (0.26 g) in methanol (5 mL) was stirredunder a hydrogen atmosphere (balloon) in the presence of 10% Pd/C (100mg) for 24 hours, and filtered through diatomaceous earth (Celite®). Thepad was washed with methanol and the combined filtrates wereconcentrated and purified by silica gel chromatography with 7%methanol/dichloromethane to provide 0.127 g of the desired product. MS(ESI(+)) m/e 258 (M+H)⁺.

EXAMPLE 337CN-[4-(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 337B and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 391 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.28 (s, 3H); 6.14 (s, 2H); 6.80 (m, 2H); 7.16 (t, J=7.8Hz, 1H); 7.25 (d, J=8.5 Hz, 1H); 7.31 (br s, 1H); 7.34 (d, J=8.5 Hz,2H); 7.57 (d, J=8.8 Hz, 2H); 8.64 (s, 1H); 8.82 (s, 1H).

EXAMPLE 338N-{4-[(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)methyl]phenyl}-N′-(3-methylphenyl)ureaEXAMPLE 338A 5-amino-3-(4-nitrobenzyl)-4-isothiazolecarbonitrile

The desired product was prepared by substituting (4-nitrophenyl)acetylchloride for 4-nitrobenzoyl chloride in Examples 96A-E. MS (ESI(−)) m/e259 (M−H)⁻.

EXAMPLE 338B N′-[4-cyano-3-(4-nitrobenzyl)-5-isothiazolyl]imidoformamide

A suspension of Example 338A (1 g, 3.8 mmol) and ammonium sulfate (50mg, 0.38 mmol) in triethylorthoformate (25 mL) was stirred at reflux for18 hours, cooled to 0° C., treated with ammonia (40 mL, 2M in propanol),stirred at room temperauture for 4 hours, and concentrated. The residuewas purified by silica gel chromatography with 35% ethyl acetate/hexanesto provide 0.38 g of the desired product. MS (ESI(−)) m/e 286 (M−H)⁻.

EXAMPLE 338C 3-(4-nitrobenzyl)isothiazolo[5,4-d]pyrimidin-4-amine

A solution of Example 338B (0.37 g, 1.29 mmol) in methanol (3 mL) wastreated with LiOCH₃ (1.4 mL, 1M in methanol), and heated to 70° C. for 4hours. The reaction was cooled to room temperature resulting in a brownprecipitate which was collected by filtration. The filter cake waswashed with cold methanol and dried to provide 0.175 g of the desiredproduct. MS (ESI(+)) m/e 288 (M+H)⁺.

EXAMPLE 338D 3-(4-aminobenzyl)isothiazolo[5,4-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 338C forExample 96F in Example 97. MS (ESI(+)) m/e 258 (M+H)⁺.

EXAMPLE 338EN-{4-[(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)methyl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 338D and3-methylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 391 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.27 (s, 3H); 4.50 (s, 2H); 6.77 (d, J=7.46 Hz, 1H);6.96 (s, 1H); 7.05-7.45 (m, 6H); 8.37 (s, 1H); 8.66 (s, 1H); 8.72 (s,1H).

EXAMPLE 339N-{4-[(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)methyl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 338D and2-fluoro-5-trifluomethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively, in Example 1F. MS (ESI(+)) m/e 463 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 4.51 (s, 2H); 7.10-7.60 (m, 6H); 8.00 (s, 1H);8.37 (s, 1H); 8.76 (s, 1H); 9.03 (s, 1H).

EXAMPLE 340N-{4-[(4-aminoisothiazolo[5,4-d]pyrimidin-3-yl)methyl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 338D and3-trifluoromethylphenyl isocyanate for Example 1E and phenyl isocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 445 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 4.52 (s, 2H); 7.16 (d, J=8.48 Hz, 2H); 7.35-7.55 (m,5H); 8.37 (s, 1H); 8.61 (dd, J=7.46, 2.71 Hz, 1H); 8.87 (d, J=2.71 Hz,1H); 9.15 (s, 1H).

EXAMPLE 341(2E)-N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-3-(3-methylphenyl)acrylamide

The desired product was prepared by substituting Example 78A and(2E)-3-(3-methylphenyl)acrylic acid for aniline and Example 66B,respectively, in Example 66C. MS (ESI(+)) m/e 415 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.17 (t, J=7.46 Hz, 3H); 2.36 (s, 3H); 2.65 (q, J=7.69Hz, 2H); 6.86 (d, J=15.60 Hz, 1H); 7.35-7.80 (m, 6H); 7.59 (d, J=15.60Hz, 1H); 7.88 (d, J=8.48 Hz, 2H); 8.27 (s, 1H); 10.28 (s, 1H).

EXAMPLE 342(2E)-N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]-3-[3-(trifluoromethyl)phenyl]acrylamide

The desired product was prepared by substituting Example 78A and(2E)-3-[3-(trifluoromethyl)phenyl]acryloyl chloride for Example 1E andbenzoyl chloride, respectively, in Example 4. MS (ESI(+)) m/e 469(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.17 (t, J=7.46 Hz, 3H); 2.65 (q,J=7.46 Hz, 2H); 7.00 (d, J=15.93 Hz, 1H); 7.39 (d, J=8.48 Hz, 2H);7.60-8.05 (m, 7H); 8.27 (s, 1H); 10.48 (s, 1H).

EXAMPLE 343 N-[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]urea

A mixture of Example 78A (0.27 g, 1 mmol) and NaOCN (0.13 g, 2 mmol) inwater (1.5 mL) and acetic acid (1.5 mL) was stirred overnight at roomtemperature and partitioned between water and ethyl acetate. The organicextract was washed with saturated aqueous NaHCO₃ and brine, dried(MgSO₄), filtered, and concentrated to provide 0.3 g of the desiredproduct. MS (ESI(+)) m/e 314 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15(t, J=7.46 Hz, 3H); 2.63 (q, J=7.57 Hz, 2H); 5.94 (m, 2H); 7.24 (d,J=8.48 Hz, 2H); 7.56 (d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.75 (s, 1H).

EXAMPLE 3443-{[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]amino}-4-[(3-methylphenyl)amino]-3-cyclobutene-1,2-dione EXAMPLE 344A3-{[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]amino}-4-ethoxy-3-cyclobutene-1,2-dione

A mixture of Example 78A (0.135 g, 0.5 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (0.22 mL, 1.5 mmol) in ethanol (5mL) was heated at 70-80° C. for 48 hours, then filtered while still hot.The filtrate was concentrated and the resulting residue was washed withhexanes and diethyl ether, and dried to provide 0.11 g of the desiredproduct. MS (ESI(+)) m/e 395 (M+H)⁺.

EXAMPLE 344B3-{[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]amino}-4-[(3-methylphenyl)amino]-3-cyclobutene-1,2-dione

A mixture of Example 344A (0.027 g, 0.068 mol) and 3-methylaniline(0.073 mL, 0.68 mmol) in ethanol (2 mL) was stirred at reflux for 48hours and concentrated. The residue was purified by silica gelchromatography with 5% methanol/dichloromethane to provide 8 mg of thedesired product. MS (ESI(+)) m/e 346 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.17 (t, J=7.46 Hz, 3H); 2.32 (s, 3H); 2.66 (q, J=7.12 Hz, 2H);6.80-7.00 (m, 2H); 7.20-7.50 (m, 4H); 7.67 (d, J=8.48 Hz, 2H); 8.28 (s,1H); 10.11 (s, 1H); 10.30 (s, 1H).

EXAMPLE 3453-{[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]amino}-4-[(3-chlorophenyl)amino]-3-cyclobutene-1,2-dione

The desired product was prepared by substituting 3-chloroaniline for3-methylaniline in Example 344B. MS (ESI(+)) m/e 476 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.17 (t, J=7.46 Hz, 3H); 2.65 (q, J=7.57 Hz, 2H); 7.14(d, J=7.46 Hz, 1H); 7.30-7.50 (m, 4H); 7.50-7.80 (m, 3H); 8.28 (s, 1H);10.14 (s, 1H); 10.24 (s, 1H).

EXAMPLE 346 ethyl{[4-(4-amino-6-ethylthieno[2,3-d]pyrimidin-5-yl)phenyl]amino}(oxo)acetate

A solution of Example 78A (0.065 g, 0.25 mmol), ethyl chloro(oxo)acetate(0.028 mL, 0.25 mmol), and pyridine (0.02 mL, 0.25 mmol) indichloromethane (5 mL) was stirred at room temperature overnight andpartitioned between water and dichloromethane. The organic extract waswashed with brine, dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by silica gel column chromatography with 5%methanol/dichloromethane to provide 60 mg of the desired product. MS(ESI(+)) m/e 371(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t, J=7.46 Hz,3H); 1.34 (t, J=7.12 Hz, 3H); 2.64 (q, J=7.46 Hz, 2H); 4.34 (q, J=7.12Hz, 2H); 7.41 (d, J=8.48 Hz, 2H); 7.93 (d, J=8.82 Hz, 2H); 8.27 (s, 1H);11.00 (s, 1H).

EXAMPLE 347 3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}isothiazolo[5,4-d]pyrimidin-4-amine

The desired product was prepared by substituting Example 97 and2-amino-4,6-dimethylphenol for Example 1E and 2-aminophenol,respectively in Example 3. MS (ESI(+)) m/e 389(M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.35 (s, 3H); 2.41 (s, 3H); 6.81 (s, 1H); 7.13 (s, 1H);7.67 (d, J=8.48 Hz, 2H); 7.96 (d, J=8.48 Hz, 2H); 8.47 (s, 1H); 10.96(s, 1H).

EXAMPLE 3483-[({[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]amino}carbonyl)amino]benzoicacid EXAMPLE 348A methyl3-[({[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]amino}carbonyl)amino]benzoate

The desired product was prepared by substituting methyl3-isocyanatobenzoate and Example 58D for phenyl isocyanate and Example1E, respectively, in Example 1F. MS(ESI(+)) m/e 420 (M+H)⁺.

EXAMPLE 348B3-[({[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]amino}carbonyl)amino]benzoicacid

A suspension of Example 348A (0.5 g, 1.19 mmol) in methanol (50 mL) andTHF (20 mL) was treated with 2N NaOH (3.6 mL, 7.2 mmol), stirred at roomtemperature for 4 hours, and heated to reflux for 1 hour. The mixturewas cooled to room temperature, diluted with water, acidified to pH 3with 4N HCl, and diluted with brine resulting in the formation of aprecipitate. The solid was collected by filtration and dried to give0.417 g of the desired product. MS (ESI(+)) m/e 406 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 7.41 (m, 3H); 7.55 (s, 1H); 7.56 (d, J=6.0 Hz, 1H);7.66-7.71 (m, 3H); 8.14 (s, 1H); 8.47 (s, 1H); 9.30 (s, 1H); 9.32 (s,1H).

EXAMPLE 349N-(4-{4-amino-6-[2-(dimethylamino)ethyl]thieno[2,3-d]pyrimidin-5-yl}phenyl)-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 281F and3,5-dimethylphenylisocyanate for Example 1E and phenylisocyanate,respectively, in Example 1F. MS (ESI(+)) m/e 461 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 2.10 (s, 6H); 2.24 (s, 6H); 2.43 (t, J=7.12 Hz, 2H);2.74 (t, J=7.12 Hz, 2H); 6.63 (s, 1H); 7.09 (s, 2H); 7.30 (d, J=8.81 Hz,2H); 7.62 (d, J=8.48 Hz, 2H); 8.26 (s, 1H); 8.59 (s, 1H); 8.86 (s, 1H).

EXAMPLE 350N-{4-[4-amino-6-(2-hydroxyethyl)thieno[2,3-d]pyrimidin-5-yl]phenyl}-2-(3-methylphenyl)acetamide

The desired product was prepared by substituting Example 104B and3-methylphenylacetic acid for aniline and Example 66B, respectively, inExample 66C. The crude product was purified by silica gel chromatographywith 7% methanol/dichloromethane to provide the desired product. m.p.142-144° C.; MS (ESI(+)) m/e 419 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.31 (s, 3H); 2.74 (t, J=6.61 Hz, 2H); 3.55 (m, 2H); 3.64 (s, 2H); 4.87(t, J=5.26 Hz, 1H); 7.07 (d, J=6.78 Hz, 1H); 7.12-7.27 (m, 3H); 7.33 (d,J=8.14 Hz, 2H); 7.77 (d, J=8.48 Hz, 2H); 8.26 (s, 1H); 10.38 (s, 1H).

EXAMPLE 351N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-hydroxyphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaEXAMPLE 351A5-[4-amino-2-(benzyloxy)phenyl]thieno[2,3-d]pyrimidin-4-amine

The desired product was prepared by substituting2-benzyloxy-4-nitro-benzoyl chloride for 3-methoxy-4-nitrobenzoylchloride in Examples 165A-D. MS (ESI(+)) m/e 348.9 (M+H)⁺.

EXAMPLE 351BN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-(benzyloxy)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 351A and2-fluoro-5-trifluoromethylphenyl isocyanate for Example 1E and phenylisocyanate, respectively in Example 1F. MS (ESI(+)) m/e 554 (M+H)⁺.

EXAMPLE 351CN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-hydroxyphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A solution of Example 351B (99 mg, 0.18 mmol) in 30% HBr/acetic acid (1mL) and acetic acid (2 mL) was stirred at 70° C. for 3 hours, cooled toroom temperature, poured into water, basified with 2N NaOH, adjusted topH to 7-8 with 1N HCl, and extracted with methanol/dichloromethane. Theextract was concentrated and the residue was purified by silica gelchromatography with 5% methanol/dichloromethane to provide 16 mg (19%yield) of the desired product. MS(ESI(+)) m/e 464.0 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 6.94 (dd, J=8.5, 2.0 Hz, 1H); 7.15 (d, J=8.1 Hz, 1H);7.31 (s, 1H); 7.38-7.43 (m, 2H, 7.48-7.55 (m, 1H); 8.30 (s, 1H); 8.64(dd, J=7.5, 2.4 Hz, 1H); 8.91 (d, J=2.7 Hz, 1H); 9.29 (s, 1H); 9.87 (s,1H)

It will be evident to one skilled in the art that the present inventionis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein X is selected fromthe group consisting of —N— and —CR³—; Z¹ is selected from the groupconsisting of —N— and —CR⁴—; z² is selected from the group consisting of—N— and —CR⁵—; Z³ is selected from the group consisting of —N— and—CR⁶—; Z⁴ is selected from the group consisting of —N— and —CR⁷—; R¹ isselected from the group consisting of hydrogen and NH₂; R² is selectedfrom the group consisting of alkoxy, cyano, hydroxy, nitro,—NR^(a)R^(b), and -LR⁸; R³ is selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkyl, arylalkyl, carboxyalkyl, halo,haloalkyl, heteroarylalkyl, (heterocyclyl)alkyl, hydroxyalkyl,(NR^(a)R^(b))alkyl, and (NR^(a)R^(b))C(O)alkyl; R⁴, R⁵, R⁶, and R⁷ areindependently selected from the group consisting of hydrogen, alkoxy,alkyl, NR^(a)R^(b), halo, and hydroxy; R⁸ is selected from the groupconsisting of alkoxyalkyl, alkyl, aryl, arylalkenyl, arylalkyl,cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and(heterocyclyl)alkyl; L is selected from the group consisting of —O—,—(CH₂)_(n)C(O)(CH₂)_(p)—, —C∉C—(CH₂)_(n)O—, —C(O)NR⁹—, —NR⁹C(O)—, —NR⁹—,—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—, —NR⁹C(S)NR¹⁰—, —NR⁹C(═NCN)NR¹⁰—,—NR⁹C(═NCN)O—, —OC(═NCN)NR⁹—, —NR⁹SO₂—, and —SO₂NR⁹—, wherein each groupis drawn with its right side attached to R⁸, and wherein R⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen, and alkyl;m, n, and p are independently 0-2; provided that at least one of Z¹, Z²,Z³, and Z⁴ is other than —N—.
 2. The compound of claim 1 wherein Z¹ is—CR⁴—; Z³ is —CR⁶—; and Z⁴ is —CR⁷—.
 3. The compound of claim 2 whereinZ² is —CR⁵—; R¹ is hydrogen; R² is -LR⁸; and m is
 0. 4. The compound ofclaim 3 wherein X is —N—.
 5. The compound of claim 3 wherein X is —CR³—.6. The compound of claim 5 wherein L is selected from the groupconsisting of —(CH₂)_(n)C(O)(CH₂)_(p)—, —C∉C—(CH₂)_(n)O—, —C(O)NR⁹—,—NR⁹C(O)—, —NR⁹—, —NR⁹C(S)NR¹⁰—, —NR⁹C(═NCN)NR¹⁰—, —NR⁹C(═NCN)O, andNR⁹SO₂—.
 7. The compound of claim 5 wherein L is—(CH₂)_(n)NR⁹C(O)NR¹⁰(CH₂)_(p)—.
 8. The compound of claim 7 wherein nand p are
 0. 9. The compound of claim 8 wherein R⁸ is aryl.
 10. Thecompound of claim 9 wherein R³ is selected from the group consisting ofalkenyl, alkoxyalkyl, arylalkyl, halo, heteroarylalkyl,heterocyclylalkyl, hydroxyalkyl, and (NR^(a)R^(b))alkyl.
 11. Thecompound of claim 9 wherein R³ is (NR^(a)R^(b))C(O)alkyl.
 12. Thecompound of claim 9 wherein R³ is hydrogen.
 13. The compound of claim 9wherein R³ is alkyl.
 14. The compound of claim 13 wherein the alkyl isselected from the group consisting of ethyl, isopropyl, and propyl. 15.The compound of claim 13 wherein the alkyl is methyl.
 16. A compoundwhich isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.17. A compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea.18. A compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea.19. A compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.20. A compound which isN-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.21. A pharmaceutical composition comprising a compound of claim 1 or atherapeutically acceptable salt thereof, in combination with atherapeutically acceptable carrier.
 22. A method for inhibiting aprotein kinase in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of claim 1, or a therapeutically acceptable saltthereof.
 23. A method for inhibiting KDR in a patient in recognized needof such treatment comprising administering to the patient atherapeutically acceptable amount of a compound of claim 1, or atherapeutically acceptable salt thereof.
 24. A method for inhibitingTie-2 in a patient in recognized need of such treatment comprisingadministering to the patient a therapeutically acceptable amount of acompound of claim 1, or a therapeutically acceptable salt thereof.
 25. Amethod for treating cancer in a patient in recognized need of suchtreatment comprising administering to the patient a therapeuticallyacceptable amount of a compound of claim 1, or a therapeuticallyacceptable salt thereof.